Triazolo[4,5-D]pyrimidinyl derivatives and their use as medicaments

ABSTRACT

The invention relates to triazolo[4,5-d]pyrimidin-3-yl derivatives which are useful in the treatment of platelet aggregation disorders.

The present invention provides new triazolo[4,5-d]pyrimidine compounds,their use as medicaments, compositions containing them and processes fortheir preparation.

Platelet adhesion and aggregation are initiating events in arterialthrombosis. Although the process of platelet adhesion to thesub-endothelial surface may have an important role to play in the repairof damaged vessel walls, the platelet aggregation that this initiatescan precipitate acute thrombotic occlusion of vital vascular beds,leading to events with high morbidity such as myocardial infarction andunstable angina. The success of interventions used to prevent oralleviate these conditions, such as thrombolysis and angioplasty is alsocompromised by platelet mediated occlusion or re-occlusion.

A number of converging pathways lead to platelet aggregation. Whateverthe initial stimulus, the final common event is a cross linking ofplatelets by binding of fibrinogen to a membrane binding site,glycoprotein IIb/IIIa (GPIIb/IIIa). The high anti-platelet efficacy ofantibodies or antagonists for GPIIb/IIIa is explained by theirinterference with this final common event. However, this efficacy mayalso explain the bleeding problems that have been observed with thisclass of agent. Thrombin can produce platelet aggregation largelyindependently of other pathways but substantial quantities of thrombinare unlikely to be present without prior activation of platelets byother mechanisms. Thrombin inhibitors such as hirudin are highlyeffective anti-thrombotic agents, but again may produce excessivebleeding because they function as both anti-platelet and anti-coagulantagents (The TIMI 9a Investigators (1994), Circulation 90, pp. 1624-1630;The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO)IIa Investigators (1994) Circulation 90, pp. 1631-1637; Neuhaus K. L.et. al. (1994) Circulation 90, pp.1638-1642).

It has been found that ADP acts as a key mediator of thrombosis. Apivotal role for ADP is supported by the fact that other agents, such asadrenaline and 5-hydroxytryptamine (SHT, serotonin) will only produceaggregation in the presence of ADP. The limited anti-thrombotic efficacyof aspirin may reflect the fact that it blocks only one source of ADPwhich is that released in a thromboxane-dependent manner followingplatelet adhesion (see e.g. Antiplatelet Trialists' Collaboration(1994), Br. Med. J. 308, pp. 81-106; Antiplatelet Trialists'Collaboration (1994), Br. Med. J. 308, pp.159-168). Aspirin has noeffect on aggregation produced by other sources of ADP, such as damagedcells or ADP released under conditions of turbulent blood flow.ADP-induced platelet aggregation is mediated by the P_(2T)-receptorsubtype uniquely located on the platelet membrane. Recently it has beenshown that antagonists at this receptor offer significant improvementsover other anti-thrombotic agents. Accordingly there is a need to findP_(2T)-antagonists as anti-thrombotic agents.

It has now been found that a series of triazolo[4,5-d]pyrimidinederivatives are P_(2T)-receptor antagonists. In a first aspect theinvention therefore provides a compound of formula (I):

wherein;

X is OH or NHR³;

R¹ is C₁₋₆-alkyl, C₃₋₈-cycloalkyl or a phenyl group, each group beingoptionally substituted by one or more halogen atoms and/or OR⁴, NR⁴R⁵,C₁₋₆-thioalkyl and/or C₁₋₆-alkyl (itself optionally substituted by oneor more halogen atoms);

R² is C₁₋₈-alkyl or C₂₋₈-alkenyl each of which is optionally substitutedby one or more halogen atoms and/or OR⁴, NR⁴R⁵, C₁₋₆-thioalkyl,C₃₋₈-cycloalkyl, aryl and/or C₁₋₆-alkyl groups; or R² is aC₃₋₈-cycloalkyl group optionally substituted by one or more halogenatoms and/or OR⁴, NR⁴R⁵, C₁₋₆-thioalkyl, phenyl and/or C₁₋₆-alkylgroups; the optional phenyl substituent being further optionallysubstituted by one or more halogen atoms and/or NO₂, C(O)R⁴, OR⁴, NR⁴R⁵,C₁₋₆-thioalkyl and/or C₁₋₆-alkyl groups;

R³ is hydrogen or C₁₋₆-alkyl substituted by one or more hydroxy and/orphenyl groups and optionally by one or more halogen atoms, wherein thephenyl group is substituted by one or more hydroxy groups and optionallysubstituted by one or more halogen atoms and/or NO₂, C(O)R⁴, OR⁴, NR⁴R⁵,C₁₋₆-thioalkyl and/or C₁₋₆-alkyl groups, or R³ is a C₁₋₆-alkyl groupsubstituted by a C(O)NR⁴R⁵ or a COOH group and optionally by one or morehalogen atoms and/or OR⁴, C(NH)NR⁴R⁵, C(O)NR⁴R⁵, phenyl and/orC₁₋₆-alkyl groups, wherein the alkyl group is optionally substituted byone or more hydroxy and/or phenyl groups and wherein the phenyl group isoptionally substituted as defined above for R³; or

R³ is a lactam ring of formula (i):

 wherein Q is a (CH₂)_(m) moiety wherein m is 1, 2 or 3, Z is O, C(O) orCH₂;

R⁴ and R⁵ each independently represent hydrogen, phenyl or a C₁₋₆-alkylwherein the alkyl group is optionally substituted by one or more phenylgroups;

or a salt thereof.

Alkyl groups, whether alone or as part of another group, can be straightchained or branched.

Suitably R¹ is C₁₋₆-alkyl, C₃₋₈-cycloalkyl or a phenyl group, each groupbeing optionally substituted by one or more halogen atoms and/or OR⁴,NR⁴R⁵, C₁₋₆-thioalkyl and/or C₁₋₆-alkyl (itself optionally substitutedby one or more halogen atoms). Preferably R¹ is C₁₋₄-alkyl,C₄₋₈-cycloalkyl or a phenyl group optionally substituted by one or morehalogen atoms or by a CF₃ group. More preferably R¹ is propyl,cyclohexyl or phenyl optionally substituted by two chlorine atoms or bya CF3 group. Most preferably R¹ is propyl or phenyl substituted in the4-position by CF₃.

Suitably R² is C₁₋₈-alkyl or C₂₋₈-alkenyl each of which is optionallysubstituted by one or more halogen atoms and/or OR⁴, NR⁴R⁵,C₁₋₆-thioalkyl, C₃₋₈-cycloalkyl, aryl and/or C₁₋₆-alkyl groups; or R² isa C₃₋₈-cycloalkyl group optionally substituted by one or more halogenatoms and/or OR⁴, NR⁴R⁵, C₁₋₆-thioalkyl, phenyl and/or C₁₋₆-alkylgroups; the optional phenyl substituent being further optionallysubstituted by one or more halogen atoms and/or NO₂, C(O)R⁴, OR⁴, NR⁴R⁵,C₁₋₆-thioalkyl and/or C₁₋₆-alkyl groups. By the term ‘aryl’ is meantphenyl and naphthyl. Preferably R² is C₁₋₆-alkyl optionally substitutedby phenyl or C₁₋₆-thioalkyl or R² is a C₃₋₈-cycloalkyl group optionallysubstituted by phenyl. Most preferably R² is butyl or2-phenylcyclopropyl.

Suitably X is OH or NHR³ where R³ is hydrogen or C₁₋₆-alkyl substitutedby one or more hydroxy and/or phenyl groups and optionally by one ormore halogen atoms, wherein the phenyl group is substituted by one ormore hydroxy groups and optionally substituted by one or more halogenatoms and/or NO₂, C(O)R⁴, OR⁴, NR⁴R⁵, C₁₋₆-thioalkyl and/or C₁₋₆-alkylgroups, or R³ is a C₁₋₆-alkyl group substituted by a C(O)NR⁴R⁵ or a COOHgroup and optionally by one or more halogen atoms and/or OR⁴,C(NH)NR⁴R⁵, C(O)NR⁴R⁵. phenyl and/or C₁₋₆-alkyl groups, wherein thealkyl group is optionally substituted by one or more hydroxy and/orphenyl groups and wherein the phenyl group is optionally substituted asdefined above, or R³ is a lactam ring of formula (i).

Preferably R³ is hydrogen or C₁₋₆-alkyl substituted by hydroxy andoptionally by C(O)NH₂ or di-fluoro; C₁₋₆-alkyl substituted by C(O)NH₂;C₁₋₆-alkyl substituted by C(O)NHMe; C₁₋₆-alkyl substituted byhydroxyphenyl and optionally by C(O)NR⁴R⁵ or R³ is a lactam ring offormula:

Most preferably R³ is hydrogen.

Particularly preferred compounds of the invention include thoseexemplified herein, both in free base form and as pharmaceuticallyacceptable salts thereof.

According to the invention there is further provided a process for thepreparation of a compound of formula (I) which comprises

(a) deprotecting a compound of formula (II):

 wherein R¹ and R² are as defined above, P¹ is a protecting group and Yis X as defined above or O—C₁₋₆-alkyl, O-benzyl or NHR wherein R is aC₁₋₆-alkyl group substituted by a C(O)OR⁸ group and optionally one ormore halogen atoms and/or OR⁴, C(NH)NR⁴R⁵, C(O)NR⁴R⁵, phenyl and/orC₁₋₆-alkyl groups, wherein R⁴ and R⁵ are as defined above and R⁸ isC₁₋₆-alkyl (for example methyl, ethyl, isopropyl or t-butyl) or benzyl;and, optionally

(b) reacting the compound of formula (I) thus obtained with a suitableacid or base to prepare a pharmaceutically acceptable salt.

The invention further provides an intermediate of formula (II) whereinits substituents are as defined above. Examples of suitable groups whicheach P¹ may independently represent are a C₁₋₆-alkyl (preferablymethyl), benzyl, (C₁₋₆-alkyl)₃Si (preferably trimethylsilyl) and aC(O)C₁₋₆-alkyl group (preferably acetyl). Preferably the two groups P¹together with the atoms to which they are attached complete a ring, forexample the two groups P¹ together represent an alkylidene such asmethylidene or, more preferably, isopropylidene, or an alkoxymethylidene such as ethoxymethylidene.

The deprotection reaction in step (a) of the process of the inventionmay be carried out using methods generally known in the art. Step (a) ispreferably carried out as follows:

(i) where one or both of P¹ represent C(O)C₁₋₆-alkyl, where Y isO-C₁₋₆-alkyl and/or where Y is NHR⁷ and R⁸ is C₁₋₆-alkyl, C(O)C₁₋₆-alkylor C₁₋₆-alkyl groups can be removed by basic hydrolysis, for example byusing a metal hydroxide, preferably an alkali metal hydroxide, such assodium hydroxide or lithium hydroxide, or quaternary ammonium hydroxidein a solvent, such as aqueous ethanol or aqueous tetrahydrofuran, at atemperature of from 10 to 100° C., preferably the temperature is aroundroom temperature; or by acidic hydrolysis using a mineral acid such asHCl or a strong organic acid such as trichloroacetic acid in a solventsuch as aqueous 1,4-dioxane;

(ii) where one or both of P¹ represent (C₁₋₆-alkyl)₃Si, they may beremoved by the use of, for example, a fluoride ion source, for exampletetra-n-butylammonium fluoride or hydrogen fluoride;

(iii) where one or both of P¹ represent a C₁₋₆-alkyl group, where Y isO—C₁₋₆-alkyl and/or where Y is NHR⁷ and R⁸ is C₁₋₆-alkyl, C₁₋₆-alkylgroups may be removed by the use of, for example, boron tribromide;

(iv) where Y is O-benzyl, where one or both of P¹ represent a benzylgroup and/or where Y is NHR⁷ and R⁸ is benzyl, benzyl groups may beremoved by hydrogenolysis using a transition metal catalyst, for examplepalladium on charcoal, under an atmosphere of hydrogen, at a pressure offrom 1 to 5 bar, in a solvent, such as acetic acid; and/or

(v) where both P¹ together represent alkylidene or an alkoxy alkylidene,they may be removed by the use of, for example, a mineral or organicacid, preferably by using trifluoroacetic acid in dichloromethane orwater at room temperature.

Deprotecting a compound of formula (II) as defined above but wherein Yis NHR⁷ wherein R⁷ is as defined above prepares a compound of formula(I) wherein X is NHR³ wherein R³ is a C₁₋₆-alkyl group substituted by aCOOH group and optionally by one or more halogen atoms and/or OR⁴,C(NH)NR⁴R⁵, C(O)NR⁴R⁵, phenyl and/or C₁₋₆-alkyl groups. Suchdeprotection is preferably carried out using a compound of formula (II)as defined above but wherein R⁸ is t-butyl and both P¹ togetherrepresent isopropylidene with trifluoroacetic acid in dichloromethane atroom temperature.

Salts of the compounds of formula (I) may be formed by reacting the freeacid, or a salt thereof, or the free base, or a salt or a derivativethereof, with one or more equivalents of the appropriate base (forexample ammonium hydroxide optionally substituted by C₁₋₆-alkyl or analkali metal or alkaline earth metal hydroxide) or acid (for exampleahydrohalic (especially HCl), sulphuric, oxalic or phosphoric acid). Thereaction may be carried out in a solvent or medium in which the salt isinsoluble or in a solvent in which the salt is soluble, e.g. water,ethanol, THF or diethyl ether, which may be removed in vacuo, or byfreeze drying. The reaction may also be ametathetical process or it maybe carried out on an ion exchange resin. The non-toxic physiologicallyacceptable salts are preferred, although other salts may be useful, e.g.in isolating or purifying the product.

To prepare a compound of formula (II) wherein Y is NHR³ and R¹, R² andP¹ are as defined above, a compound of formula (II) wherein Y is OH andR¹, R² and P¹ are defined above is reacted with R³NH₂ wherein R³ is asdefined above. The reaction is preferably carried out in the presence ofa coupling agent using methods known from peptide synthesis (see M.Bodanszky and A. Bodanszky, The Practice of Peptide Synthesis,Springer-Verlag, 1984). Suitable coupling agents include1,1′-carbonyldiimidazole and dicyclohexylcarbodiimide; the preferredcoupling agent is bromo-tris-pyrrolidino-phosphonium hexafluorophosphateorbenzotriazole-1-yl-oxy-tris-(dimethylamino)phosphoniumhexafluorophosphate,used in the presence of N,N-diethylisopropylamine. The reaction ispreferably carried out in N,N-dimethylformamide (DMF) or tetrahydrofuran(THF) and preferably at a temperature of from −15° to 120° C., morepreferably at a temperature of from 0° C. to room temperature. Thisreaction may correspondingly be used to convert a compound of formula(I) wherein X is OH and R¹ and R³ are as defined above to a compound offormula (I) wherein X is NHR³ and R¹, R² and R³ are as defined above.

To prepare a compound of formula (II) as defined above but where Y isNHR⁷ wherein R⁷ is as defined above, a compound of formula (II) whereinY is OH is reacted with a compound of formula R⁷NH₂ wherein R⁷ is asdefined above, using the coupling conditions described above.

A compound of formula (II) as defined above but wherein Y is NHR³wherein R³ is a C₁₋₆-alkyl group substituted by a C(O)NR⁴R⁵ group andoptionally by one or more halogen atoms and/or OR⁴, C(NH)NR⁴R⁵,C(O)NR⁴R⁵, phenyl and/or C₁₋₆-alkyl groups, may be prepared by reactinga compound of formula (II) as defined above but wherein Y is NHR³wherein R³ is a C₁₋₆-alkyl group substituted by a COOH group andoptionally by one or more halogen atoms and/or OR⁴, C(NH)NR⁴R⁵,C(O)NR⁴R⁵, phenyl and/or C₁₋₆-alkyl groups, with HNR⁴R⁵ wherein R⁴ andR⁵ are as defined above in the presence of a coupling agent as definedabove. This reaction may also be used to convert a compound of formula(I) as defined above but wherein X is NHR³ wherein R³ is a C₁₋₆-alkylgroup substituted by a COOH group and optionally by one or more halogenatoms and/or OR⁴, C(NH)NR⁴R⁵, C(O)NR⁴R⁵, phenyl and/or C₁₋₆-alkyl groupsto a compound of formula (I) as defined above but wherein X is NHR³wherein R³ is a C₁₋₆-alkyl group substituted by a C(O)NR⁴R⁵ group andoptionally by one or more halogen atoms and/or OR⁴, C(NH)NR⁴R⁵,C(O)NR⁴R⁵, phenyl and/or C₁₋₆-alkyl groups.

A compound of formula (II) as defined above but wherein Y is NHR³wherein R³ is a C₁₋₆-alkyl group substituted by a COOH group andoptionally by one or more halogen atoms and/or OR⁴, C(NH)NR⁴R⁵,C(O)NR⁴R⁵, phenyl and/or C₁₋₆-alkyl groups wherein R⁴ and R⁵ are asdefined above, may be prepared by deprotecting a compound of formula(II) as defined above but wherein Y is NHR⁷ using the deprotectionprocedures given in (i), (iii) or (iv) above.

A compound of formula (II) wherein Y is NHR³ or NHR⁷ can be prepared byfirst activating a compound of formula (II) wherein Y is OH and thentreating it with R³NH₂ or R⁷NH₂ wherein R³ and R⁷ as defined above, or asalt thereof. The treatment is generally carried out in an inert solventat a temperature of from −20 to 150° C.

Methods of activating a compound of formula (II) wherein Y is OH includeformation of an acyl halide or an acetic anhydride. Acid anhydrides maybe formed by treatment with an acyl halide, such as acetyl chloride inthe presence of a base, such as pyridine or by treatment with adehydrating agent such as acetic acid anhydride or phosphorus pentoxidein an inert solvent. Acyl halides may be formed by treatment of the acidwith a halogenating agent, for example P(III), P(V) or S(IV) halidessuch as phosphorus trichloride. Acyl halides may also be prepared by anexchange reaction of the acid with an acyl halide such as oxalylbromide. The reactions may be performed in the halogenating agent oracyl halide as solvent or in other inert solvents such as methylenechloride, at a temperature of from 0 to 150° C. Activation is preferablycarried out by treatment with oxalyl chloride in dichloromethane at roomtemperature.

The substituent R¹ in the compound of formula (II) may optionally bereplaced by first oxidising the compound of formula (II) to a compoundof formula III:

wherein R¹, P¹, Y and R² are as defined above and n is 1 or 2, using anorganic oxidant such as dimethyldioxirane or an inorganic oxidant suchas sodium hypochlorite in an inert solvent, such as dichloromethane or amixture of methanol and water, at a temperature of from −20 to 40° C.,preferably the oxidant is either Oxone (registered trademark) and thereaction is carried out in acetonitrile/water at room temperature or theoxidant is 3-chloroperoxybenzoic acid and the reaction is carried out indichloromethane. This reaction may correspondingly be used to change thesubstituent R¹ in a compound of formula (I).

The compound of formula (III) is then treated with a compound of formulaR¹SM wherein R¹ is as defined above and M is an alkali metal, forexample lithium or potassium, to give a compound of formula (II) with adifferent substituent R¹. The reaction is generally carried out in aninert solvent at a temperature of from −20 to 40° C. M is preferablysodium and the reaction is preferably carried out in tetrahydrofuran atroom temperature.

A compound of formula R¹SM may be prepared by reacting R¹SH with a basesuch as C₁₋₆-alkyl-M or MH, wherein M is as defined above, in an inertsolvent at a temperature of from −20 to 40° C.

A compound of formula (II) wherein Y is OH, O—C₁₋₆-alkyl or O-benzyl canbe prepared by reacting a compound of formula IV:

wherein R¹ and P¹ are as defined above, L¹ is a leaving group, forexample a halogen atom and R⁹ is a H atom or a C₁₋₆-alkyl or benzylgroup, with NH₂R₂ or a salt of NH₂R² wherein R² is as defined above, inthe presence of a base. Suitable salts of NH₂R² include hydrochlorides.Suitable bases include an organic base such as triethylamine or aninorganic base such as potassium carbonate.

A compound of formula (IV) can be prepared by diazotising a compound offormula V:

wherein R¹, R⁹, L¹ and P¹ are as defined above, with a metal nitrite,for example an alkali metal nitrite, especially sodium nitrite in diluteaqueous acid, for example 2M HCl, or with a C₁₋₆-alkyl nitrite in aninert solvent, at a temperature of from −20 to 100° C.; preferredconditions are isoamyl nitrite in acetonitrile at 80° C.

A compound of formula (V) wherein R⁹ is H can be prepared by reducingand hydrolysing a compound of formula VI:

wherein R¹, L¹ and P¹ are as defined above. The reduction may be carriedfor example by using hydrogenation with a transition metal catalyst at atemperature around room temperature, for example palladium on charcoalunder an atmosphere of hydrogen, preferably at a pressure from 1 to 5atmospheres, in a solvent, for example ethanol, or by using iron in anacidic solvent such as acetic acid at a temperature of about 100° C.

To prepare a compound of formula (V) wherein R⁹ is H, hydrolysis of thecompound of formula (VI) may be performed by using a mineral acid suchas HCl or a strong organic acid such as trifluoroacetic acid in asolvent such as aqueous 1,4-dioxane, at a temperature of from 20 to 150°C. Preferably the reduction and hydrolysis are carried outsimultaneously using iron in an acidic solvent, for example acetic acid,containing an alkaline earth metal halide, for example calcium chloride,at a temperature of about 80° C.

To prepare a compound of formula (V) wherein R⁹ is C₁₋₆-alkyl or benzyl,the compound of formula (VI) is treated with iron in acetic acid at atemperature of from 50 to 80° C. so that the nitro group is reduced. Theresulting intermediate is then treated with sodium borohydride in amixture of water and C₁₋₆-alkyl alcohol or benzyl alcohol at around roomtermperature.

A compound of formula (VI) can be prepared by reacting a compound offormula VII:

wherein L¹ and R¹ are as defined above and L² is a leaving group, forexample a halogen atom, wherein L¹ and L² are preferably the same, witha compound of formula VIII:

wherein P¹ is as defined above, in the presence of a base such asC₁₋₆-alkyl-M or MH wherein M is as defined above, for example butyllithium, in an inert solvent, such as tetrahydrofuran (THF), at atemperature of from −10 to 100° C. Preferably sodium hydride is used inTHF at room temperature.

A compound of formula (VII) may be prepared from4,6-dihydroxy-2-mercaptopyrimidine by alkylation with R¹L³ wherein R¹ isas defined above and L³ is a suitable leaving group, for example ahalogen atom, followed by nitration, whereafter the two alcohols areconverted to leaving groups L¹ and L².

All novel intermediates form an aspect of the invention. In particularthe invention further provides an intermediate of formula (III) whereinR¹, R², P¹, n and Y are as defined above.

The compounds of the invention act as P₂₇-receptor antagonists.Accordingly, the compounds are useful in therapy, especially adjunctivetherapy, particularly they are indicated for use as: inhibitors ofplatelet activation, aggregation and degranulation, anti-thromboticagents or in the treatment or prophylaxis of unstable angina, coronaryangioplasty (PTCA), myocardial infarction, perithrombolysis, primaryarterial thrombotic complications of atherosclerosis such as thromboticor embolic stroke, peripheral vascular disease, myocardial infarctionwith or without thrombolysis, arterial complications due tointerventions in atherosclerotic disease such as angioplasty,endarterectomy, stent placement, coronary and other vascular graftsurgery,thrombotic complications of surgical or mechanical damage suchas tissue salvage following accidental or surgical trauma,reconstructive surgery including skin and muscle flaps, conditions witha diffuse thrombotic/platelet consumption component such as disseminatedintravascular coagulation, thrombotic thrombocytopaenic purpura,haemolytic uraemic syndrome, thrombotic complications of septicaemia,adult respiratory distress syndrome, anti-phospholipid syndrome,heparin-induced thrombocytopaenia and pre-eclampsia/eclampsia, or venousthrombosis such as deep vein thrombosis, venoocclusive disease,haematological conditions such as myeloproliferative disease, includingthrombocythaemia; or in the prevention of mechanically-induced plateletactivation in vivo, such as cardiopulmonary bypass (prevention ofmicrothromboembolism), mechanically-induced platelet activation invitro, such as use in the preservation of blood products, e.g. plateletconcentrates, or shunt occlusion such as in renal dialysis andplasmapheresis, thrombosis secondary to vascular damage/inflammationsuch as vasculitis, arteritis, glomerulonephritis, inflammatory boweldisease and organ graft rejection, conditions such as migraine,Raynaud's phenomenon, atheromatous plaque formation/progression,vascular stenosis/restenosis and asthma, in which platelet-derivedfactors are implicated in the disease process.

According to the invention there is further provided the use of acompound according to the invention in the manufacture of a medicamentfor the treatment of the above disorders, in particular a plateletaggregation disorder. The invention also provides a method for thetreatment of the above disorders, in particular a platelet aggregationdisorder which comprises administering to a patient suffering from sucha disorder a therapeutically effective amount of a compound according tothe invention.

The compounds may be administered topically, e.g. to the lung and/or theairways, in the form of solutions, suspensions, HFA aerosols and drypowder formulations; or systemically, e.g. by oral administration in theform of tablets, pills, capsules, syrups, powders or granules, or byparenteral administration in the form of sterile parenteral solutions orsuspensions, or by rectal administration in the form of suppositories ortransdermally.

The compounds of the invention may be administered on their own or as apharmaceutical composition comprising the compound of the invention incombination with a pharmaceutically acceptable diluent, adjuvant orcarrier.

Dry powder formulations and pressurized HFA aerosols of the compounds ofthe invention may be administered by oral or nasal inhalation. Forinhalation the compound is desireably finely divided. The finely dividedcompound preferably has a mass median diameter of less than 10 μm, andmay be suspended in a propellant mixture with the assistance of adispersant, such as a C₈-C₂₀ fatty acid or salt thereof, (e.g. oleicacid), a bile salt, a phospholipid, an alkyl saccharide, aperfluorinated or polyethoxylated surfactant, or other pharmaceuticallyacceptable dispersant.

The compounds of the invention may also be administered by means of adry powder inhaler. The inhaler may be a single or a multi dose inhaler,and may be a breath actuated dry powder inhaler.

One possibility is to mix the finely divided compound with a carriersubstance, e.g. a mono-, di- or polysaccharide, a sugar alcohol oranother polyol. Suitable carriers are sugars, e.g. lactose, glucose,raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol;and starch. Alternatively the finely divided compound may be coated byanother substance. The powder mixture may also be dispensed into hardgelatine capsules, each containing the desired dose of the activecompound.

Another possibility is to process the finely divided powder into sphereswhich break up during the inhalation procedure. This spheronized powdermay be filled into the drug reservoir of a multidose inhaler, e.g. thatknown as the Turbuhaler® in which a dosing unit meters the desired dosewhich is then inhaled by the patient. With this system the activecompound with or without a carrier substance is delivered to thepatient.

The pharmaceutical composition comprising the compound of the inventionmay conveniently be tablets, pills, capsules, syrups, powders orgranules for oral administration; sterile parenteral solutions orsuspensions for parenteral administration or suppositories for rectaladministration.

For oral administration the active compound may be admixed with anadjuvant or a carrier, e.g. lactose, saccharose, sorbitol, mannitol,starches such as potato starch, corn starch or amylopectin, cellulosederivatives, a binder such as gelatine or polyvinylpyrrolidone, and alubricant such as magnesium stearate, calcium stearate, polyethyleneglycol, waxes, paraffin, and the like, and then compressed into tablets.If coated tablets are required, the cores, prepared as described above,may be coated with a concentrated sugar solution which may contain e.g.gum arabic, gelatine, talcum, titanium dioxide, and the like.Alternatively, the tablet may be coated with a suitable polymerdissolved in a readily volatile organic solvent.

For the preparation of soft gelatine capsules, the compound may beadmixed with e.g. a vegetable oil or polyethylene glycol. Hard gelatinecapsules may contain granules of the compound using either the abovementioned excipients for tablets, e.g. lactose, saccharose, sorbitol,mannitol, starches, cellulose derivatives or gelatine. Also liquid orsemisolid formulations of the drug may be filled into hard gelatinecapsules.

Liquid preparations for oral application may be in the form of syrups orsuspensions, for example solutions containing the compound, the balancebeing sugar and a mixture of ethanol, water, glycerol and propyleneglycol. Optionally such liquid preparations may contain colouringagents, flavouring agents, saccharine and carboxymethylcellulose as athickening agent or other excipients known to those skilled in art.

The invention is illustrated by the following examples which should notbe interpreted as limiting the invention. In the examples the NMRspectra were measured on a Varian Unity Inova 300 spectrometer and theMS spectra were measured as follows: EI spectra were obtained on a VG70-250S or Finnigan Mat Incos-XL spectrometer, FAB spectra were obtainedon a VG70-250SEQ spectrometer, ESI and APCI spectra were obtained onFinnigan Mat SSQ7000 or a Micromass Platform spectrometer. PreparativeHPLC separations were generally performed using a Novapak®, Bondapak® orHypersil® column packed with BDSC-18 reverse phase silica. Flashchromatography (indicated in the Examples as (SiO₂)) was carried outusing Fisher Matrix silica, 35-70 μm.

EXAMPLE 1[1S-(1α,2β,3β,4α)]-4-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide

(a) 4,6-Dihydroxy-2-(propylthio)pyrimidine

Propyl iodide (136 ml) was added to a suspension of4,6-dihydroxy-2-mercaptopyrimidine (200 g) in water (800 ml), containingsodium hydroxide (55.6 g). The reaction mixture was stirred for 2 weeksthen concentrated to half volume, 2N hydrochloric acid was added and thesubtitle compound was isolated by filtration (167 g).

MS (EI) 186 (M⁺, 100%).

(b) 4,6-Dihydroxy-5-nitro-2-(propylthio)pyrimidine

The product of step (a) (70 g) was added slowly to ice-cooled fumingnitric acid (323 ml). The reaction mixture was stirred for 1 hour thenpoured onto ice and the subtitle compound was isolated by filtration (65g).

MS (EI) 231 (M⁺), 41 (100%).

(c) 4,6-Dichloro-5-nitro-2-(propylthio)pyrimidine

N,N-Diethylaniline (150 ml) was added dropwise to a stirred suspensionof the product of step (b) (134 g) in phosphoryl chloride (500 ml) thenthe resulting solution heated at reflux for 1 hour. The cooled reactionmixture was poured onto ice then extracted with diethyl ether (3×500ml). The combined extracts were dried and concentrated. Chromatography(SiO₂, isohexane: diethyl ether, 19:1 as eluant) gave the subtitlecompound (128 g).

MS (EI) 271, 269, 267 (M⁺), 41 (100%).

(d)[3aS-(3aα,4β,7β,7aα)]5-[6-Chloro-5-nitro-2-(propylthio)pyrimidin-4-yl]-tetrahydro-2,2-dimethyl-4,7-methano-1,3-dioxolo[4,5-c]pyridin-6(3aH)-one

Sodium hydride (60%, 4.00 g) was added portionwise to[3aS-(3aα,4β,7β,7aα]tetrahydro-2,2-dimethyl-4,7-methano-1,3-dioxolo[4,5-c]pyridin-6(3aH)-one(18.3 g) in THF (500 ml). On stirring for 1 hour the solution was addeddropwise to the product of step (c) (54.0 g) in THF (500 ml). Thereaction mixture was stirred at room temperature for 45 minutes thenconcentrated and purified by chromatography (SiO₂, dichloromethane:isohexane, 3:2 as eluant) to afford the subtitle compound (79.2 g).

MS (APCI) 417, 415 (M+H⁺), 415 (100%).

(e)[3aR-(3aα,4α,6α,6aα)]-6-[[5-Amino-6-chloro-2-(propylthio)-4-pyrimidinyl]amino]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxylicacid

Iron powder (10.0 g) was added to a stirred solution of the product ofstep (d) (100 g), and calcium chloride (1.49 g) in ethanol (140 ml). Thereaction mixture was heated at reflux for 10 minutes then filteredthrough celite, washing several times with hot ethanol. The filtrate wasconcentrated to afford the subtitle compound (9.3 g).

MS (FAB) 405, 403 (M+H⁺), 405 (100%).

(f)[3aR-(3aα,4α,6α,6aα)]-6-[7-Chloro-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxylicacid

Isoamyl nitrite (6.02 ml) was added to a solution of the product of step(e) (9.28 g) in acetonitrile (80 ml) and the solution heated at 70° C.for 1 hour. The cooled reaction mixture was concentrated and purified(SiO₂, ethyl acetate:isohexane 2:1 as eluant) to afford the subtitlecompound (7.9 g).

MS (FAB) 416, 414 (M+H⁺), 414 (100%).

(g)[3aR-(3aα,4α,6α,6aα)]-6-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3dioxole-4-carboxylcacid

The product from step (f) (5.52 g) and butylamine (5 ml) in 1,4-dioxane(25 ml) were stirred at room temperature for 1 hour. The reactionmixture was concentrated and the residue purified (SiO₂,dichloromethane:ethyl acetate 2:1 as eluant) to afford the subtitlecompound (2.2 g).

MS (FAB) 451 (M+H⁺, 100%).

(h)[3aR-(3aα,4α,6α,6aα)]-6-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide

Oxalyl chloride (0.24 ml) was added dropwise to a solution of theproduct of step (g) (0.60 g) in dichloromethane (15 ml) and the solutionstirred at room temperature for 2 hours then concentrated. The residuewas taken into dichloromethane (10 ml) cooled to 0° C. and 880 ammonia(10 ml) added, then the solution stirred at room temperature for 18hours. The resulting solid was collected by filtration and dried undervacuum to afford the subtitle compound (0.48 g).

MS (FAB) 438 (M+H⁺, 100%).

(i)[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxycyclopentanecarboxamide

A solution of the product from step (h) (0.48 g) in trifluoroacetic acid(9 ml)/water (1 ml) was stirred at room temperature for 5 hours. Thereaction mixture was concentrated and the residue purified bychromatography (SiO₂, dichloromethane:methanol, 15:1 as eluant) toafford the title compound (0.17 g).

Melting point: 209-211° C. (EtOAc);

NMR δH (d₆-DMSO) 8.96 (1H, t), 7.40-6.90 (2H, m), 5.03-4.96 (2H, m),4.22 (1H, m), 3.89 (1H, m), 3.40 (2H, m), 2.80 (2H, m), 2.43-2.31 (2H,m), 1.73-1.51 (4H, m), 1.37-1.31 (2H, m), 0.98 (3H, t), 0.90 (3H, t).

EXAMPLE 2[1S-(1α,2β,3β,4α)]-4-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid

Prepared according to the method of Example 1 step (i) using the productof Example 1 step (g).

NMR δH (d₆-DMSO) 9.01-8.98 (1H, t), 5.03-4.96 (1H, m), 4.42-4.39 (1H,m), 4.21 (1H, m), 3.89 (1H, m), 3.52-3.46 (2H, m), 3.15-3.03 (2H, m),1.73-1.55 (4H, m), 1.37-1.31 (2H, m), 0.98 (3H, t), 0.91 (3H, t);

MS (FAB) 411 (M+H⁺, 100%).

EXAMPLE 3[1S-(1α,2β,3β,4α)]-4-[7-(cyclopropylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide

(a)[3aR-(3aα,4α,6α,6aα)]-6-[7-(Cyclopropylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxylicacid

Prepared according to the method of Example 1 step (g) using the productof Example 1 step (f) and cyclopropylamine.

NMR δH (d₆-DMSO) 7.95 (1H, d), 5.72 (1H, m), 5.58 (1H, m), 5.12 (1H, d),3.36-3.01 (2H, m), 3.02-2.88 (2H, m), 2.60-2.46 (1H, m), 1.88-1.78 (2H,m), 1.56 (3H, s), 1.45 (3H, s), 1.10 (3H, t), 0.75 (2H, t), 0.38 (2H, brs).

(b)[3aR-(3aα,4α,6α,6aα)]-6-[7-(Cyclopropylamino)-5-(propylthio)-3H-1,2,3-triazol[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide

Prepared according to the method of Example 1 step (h) using the productof step (a).

MS (FAB) 434 (M+H⁺, 100%).

(c)[1S-(1α,2β,3β,4α)]-4-[7-(Cyclopropylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide

Prepared according to the method of Example 1 step (i) using the productof step (b).

MS (FAB) 394 (M+H⁺, 100%).

EXAMPLE 4[1S-(1α,2β,3β,4α)]-4-[7-(cyclopropylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-dlpyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid

Prepared according to the method of Example 1 step (i) using the productof Example 3 step (a).

MS (APCI) 395 (M+H⁺, 100%);

NMR δH (d₆-DMSO) 9.10 (1H, d), 5.07 (1H, m), 4.45 (1H, m), 4.42 (1H, m),3.26-3.00 (3H, m), 2.80 (1H, t), 2.57-2.43 (2H, m), 1.74 (2H, m), 1.01(3H, t), 0.94-0.72 (4H, m).

EXAMPLE 5[1S-[1α,2β,3β,4α(trans)]]-2,3-dihydroxy-4-[7-[(2-phenylcyclopropyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxylicacid

(a)[3aR-[3aα,4α,6α(trans),6aα]]-6-[7-[2-Phenylcyclopropyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxylicacid

Prepared according to the method of Example 1 step (g) using the productof Example 1 step (f), (trans) 2-phenylcyclopropylamine hydrochlorideand triethylamine.

MS (APCI) 511 (M+H⁺, 100%).

(b)[1S-(1α,2β,3β,4α)]-4-[(2-Phenylcyclopropyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid

Prepared according to the method of Example 1 step (i) using the productof step (a).

MS (APCI) 471 (M+H⁺, 100%); NMR δH (d₆-DMSO) 9.36 (1H, d), 7.31-7.15(5H, m), 5.01 (1H, q), 4.40 (1H, m), 4.21 (1H, m), 3.19 (1H, m),2.91-2.82 (3H, m), 2.51-2.13 (4H, m), 1.53-1.48 (2H, m), 1.34 (1H, m),0.81 (2H, m).

EXAMPLE 6[1S-[1α,2β,3β,4α(trans)]]-2,3-dihydroxy-4-[7-[(2-phenylcyclopropyl)-amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxamide

Prepared according to the method of Example 1 step (h) using the productof Example 5 and purified by flash chromatography (SiO₂,chloroform:methanol 93:7 as eluant).

MS (APCI) 470 (M+H⁺, 100%); NMR δH (d₆-DMSO) 9.36 (1H, d), 7.39 (1H, s),7.29 (2H, m), 7.18 (3H, m), 6.93 (1H, s), 5.12 (1H, d), 4.99 (1H, d),4.96 (1H, m), 4.39 (1H, m), 4.11 (1H, q), 3.20 (1H, m), 2.89 (2H, m),2.74 (1H, m), 2.28 (2H, m), 2.13 (1H, m), 1.47 (3H, m), 1.34 (1H, m),0.81 (3H, t).

EXAMPLE 7[1S-[1α,2β,3β,4α)]]-2,3-dihydroxy-4-[7-(2-phenylethylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxylicacid

(a)[3aS-(3aα,4β,7β,7aα)]5-[5-amino-6-chloro-2-(propylthio)-pyrimidin-4-yl]-tetrahydro-2,2-dimethyl-4,7-methano-1,3-dioxolo[4,5-c]pyridin-6(3aH)-one

Reduced iron powder (50 g) was added to a solution of the product ofExample 1 step (d) (50.0 g) in glacial acetic acid (1800 ml) and thereaction mixture heated at reflux for 15 minutes. The cooled reactionmixture was concentrated and the residue taken into ether (300 ml) thenwashed with sodium bicarbonate solution (2×200 ml). The organic phasewas dried and concentrated and the residue purified (SiO₂,dichloromethane:diethyl ether 9:1 as eluant) to afford the subtitlecompound (42.6 g).

(b)[3aR-(3aα,4α,6α,6aα)]-6-[[5-Amino-6-chloro-2-(propylthio)-4-pyrimidinyl]amino]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxylicacid, methyl ester

Sodium borohydride (0.60 g) was added, over 30 minutes to an ice-cooledsolution of the product of step (a) (4.50 g) in methanol (100 ml). Thesolution was concentrated and purified by chromatography (SiO₂,dichloromethane: ethyl acetate, 95:5 as eluant) to give the subtitlecompound (2.1 g).

MS (APCI) 419, 417 (M+H⁺), 417 (100%).

Further elution gave[3aR-(3aα,4α,6α,6aα)]-6-[[5-amino-6-chloro-2-(propylthio)-4-pyrimidinyl]amino]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol(2.4 g).

MS (APCI) 419, 417 (M+H⁺), 417 (100%).

(c)[3aR-(3aα,4α,6α,6aα)]-6-[7-Chloro-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxylicacid, methyl ester

Prepared according to the method of Example 1 step (f) using the productof step (b).

MS (FAB) 430, 428 (M+H⁺), 417 (100%).

(d)[3aR-(3aα,4α,6α,6aα)]-6-[7-(2-Phenylethylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxylicacid, methyl ester

Prepared according to the method of Example 1 step (g) using the productof step (c), phenylethylamine hydrochloride and potassium carbonate.

MS (APCI) 513 (M+H⁺, 100%).

(e)[1S-(1α,2β,3β,4α)]-4-[7-(2-Phenylethylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid, methyl ester

Prepared according to the method of Example 1 step (i) using the productof step (d).

MS (APCI) 473 (M+H⁺, 100%).

(f)[1S-(1α,2β,3β,4α)]-4-[7-(2-Phenylethylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxycyclopentanecarboxylicacid

Lithium hydroxide monohydrate (56 mg) was added to a solution of theproduct of step (e) (0.25 g) in THF (30 ml)/water (30 ml). The solutionwas stirred at room temperature for 18 hours then 2M HCl (aq) addeduntil the pH was 7 before extracting with ethyl acetate (3×40 ml). Thecombined organics were dried and concentrated to afford the titlecompound.

MS (APCI) 459 (M+H⁺, 100%); Elemental analysis Found C: 54.77; H: 5.72;N: 18.00; S: 7.34% Required C: 55.00; H: 5.72; N: 18.30; S: 7.00%

EXAMPLE 8[1S-(1α,2β,3β,4α)]-2,3-dihydroxy-4-[7-(2-phenylethylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxamide

Prepared according to the method of Example 1 step (h) using the productof Example 7.

NMR δH (d₆-DMSO) 9.10 (1H, d), 7.31 (1H, s), 7.30-7.15 (4H, m), 6.94(1H, s), 5.14 (1H, d), 5.00 (1H, d), 5.004.90 (1H, m), 4.45-4.30 (lH,m), 4.20-4.00 (1H, m), 3.80-3.60 (2H, m), 3.20-3.00 (2H, m), 3.00-2.90(2H, m), 2.80-2.70 (1H, m), 2.40-2.10 (2H, m), 1.75-1.60 (2H, m), 0.97(3H, t).

EXAMPLE 9[1S-(1α,2β,3β,4α)]-2,3-dihydroxy-4-[7-[2-(methylthio)ethylaminol-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxylicacid

The product of Example 1 step (f) (2.0 g) and 2-(methylthio)ethylamine(0.91 g) in 1,4-dioxane (25 ml) were stirred at room temperature for 1hour. The reaction mixture was concentrated and the residue taken intotrifluoroacetic acid (20 ml)/water (10 ml) then stirred at roomtemperature for 1 hour. The reaction mixture was concentrated and theresidue purified by chromatography (HPLC, Nova-pak® C18 column, 0.1%ammonium acetate:methanol, 60:40 as eluant) to afford the product (0.17g).

MS (APCI) 429 (M+H⁺, 100%); NMR δH (d₆-DMSO) 5.00 (1H, m), 4.44 (1H, m),4.19 (1H, m), 3.71 (2H, m), 3.01 (2H, m), 2.78-2.65 (3H, m), 2.35 (2H,t), 2.12 (3H, s), 1.74 (2H, m), 0.98 (3H, m).

EXAMPLE 10[1S-(1α,2β,3β,4α)]-2,3-dihydroxy-4-[7-[2-(methylthio)ethylamino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxamide

Prepared according to the method of Example 1 step (h) using the productof Example 9.

MS (APCI) 428 (M+H⁺, 100%);

NMR δH (d₆-DMSO) 9.07 (1H, t), 8.66 (1H, t), 7.38 (IH, s), 6.93 (1H, s),5.15 (2H, br s), 4.97 (1H, m), 4.46 (1H, m), 4.12 (1H, m), 3.70 (2H, m),3.10 (2H, m), 2.75 (3H, m), 2.39-2.18 (2H, m), 1.70 (2H, m), 1.00 (3H,t).

EXAMPLE 11[1S-[1α,2β,3β,4α(trans)]]-4-[5-(Cyclohexylthio)-7-[2-(phenylcyclopropyl)amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid

(a)[3aR-[3aα,4α,6α,6aα(trans)]]-Tetrahydro-2,2-dimethyl-6-[7-(2-phenylcyclopropylamino)-5-(propylsulfonyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-4H-cyclopenta-1,3-dioxole-4-carboxylicacid

3-Chloroperoxybenzoic acid (0.14 g) was added to a solution of theproduct of Example 5 step (a) (0.11 g) in dichloromethane (8 ml) and theresulting solution stirred at room temperature for 18 hours. Thesolution was washed with aqueous sodium metabisulfite solution (3×10 ml)then dried and concentrated. Purification by chromatography (SiO₂, ethylacetate: isohexane, 1:1 as eluant) gave the subtitle compound (0.12 g).

MS (APCI) 543 (M+H⁺, 100%).

(b)[3aR-[3aα,4α,6α,6aα(trans)]]-6-[5-(cyclohexylthio)-7-[2-phenylcyclopropyl)amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxylicacid

Cyclohexanethiol (0.16 g) was added dropwise to a suspension of sodiumhydride (60%, 55 mg) in N,N-dimethylformamide (DMF) (10 ml). After 30minutes, a solution of the product of step (a) (0.30 g) in DMF (10 ml)was added dropwise over 45 minutes then the reaction was stirred for 45minutes. The reaction mixture was added slowly to a solution of sodiumchloride (10 ml), containing acetic acid (1 ml) then the solutionextracted with ethyl acetate (50 ml). The organic phase was dried andconcentrated and the residue purified by chromatography (SiO₂, ethylacetate: isohexane, 2:1 as eluant) to give the subtitle compound (0.26g).

MS (APCI) 551 (M+H⁺, 100%).

(c)[1S-[1α,2β,3β,4α(trans)]]-4-[5-(Cyclohexylthio)-7-[2-(phenylcyclopropyl)amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid

Prepared according to the method of Example 1 step (i) using the productof step (b).

MS (APCI) 511 (M+H⁺, 100%); NMR δH (d₆-DMSO) 12.42 (1H, s), 7.29 (2H,m), 7.18 (3H, m), 5.16 (2H, m), 5.00 (1H, q), 4.42 (1H, m), 4.22 (1H,q), 3.58 (1H, m), 3.20 (1H, m), 2.82 (1H, m), 2.40 (2H, m), 2.15 (IH,m), 1.94 (1H, m), 1.79 (1H, m), 1.57-1.18 (10H, m).

EXAMPLE 12[1S-[1α,2β,3β,4α(trans)]]-2,3-Dihydroxy-4-[7-[(2-phenylcyclopropyl)amino]-5-(cyclohexylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxamide

Prepared according to the method of Example 1 step (h) using the productof Example 11.

MS (APCI) 510 (M+H⁺, 100%); NMR δH (d₆-DMSO) 9.32 (1H, d), 7.37 (1H, s),7.29 (2H, m), 7.18 (3H, m), 6.92 (1H, s), 5.11 (1H, d), 4.93 (2H, m),4.40 (1H, q), 4.12 (1H, m), 3.60 (1H, m), 3.20 (1H, m), 2.75 (1H, m),2.28 (2H, m), 2.14 (1H, m), 1.92 (1H, m), 1.77 (1H, m), 1.57-1.18 (10H,m).

EXAMPLE 13[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(3,4-dichlorophenylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid

(a)[3aR-(3aα,4α,6α,6aα)]-6-[7-(Butylamino)-5-(propylsulfonyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxylicacid

Prepared according to the method of Example 11 step (a) using theproduct of Example 1 step (g).

MS (APCI) 483 (M+H⁺), 349 (100%).

(b)[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(propylsulfonyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid

Prepared according to the method of Example 1 step (i) using the productof step (a).

MS (APCI) 443 (M+H⁺, 100%).

(c)[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(3,4-dichlorophenylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid

Prepared according to the method of Example 11 step (b) using theproduct of step (b) and 3,4-dichlorothiophenol.

MS (APCI) 517, 515, 513 (M+H⁺), 513 (100%); NMR δH (d₆-DMSO) 12.40 (1H,br s), 9.15 (1H, t), 7.94 (1H, s), 7.72 (1H, d), 7.61 (1H, d), 4.97-4.94(1H, m), 4.36-4.33 (1H, m), 4.19-4.16 (1H, m), 3.21-3.14 (2H, m),2.82-2.78 (1H, m), 2.51-2.44 (1H, m), 2.26-2.21 (1H, m), 1.33 (2H, q),1.13 (2H, q), 0.79 (3H, t).

EXAMPLE 14[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(3,4-dichlorophenylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide

Prepared according to the method of Example 1 step (h) using the productof Example 13.

MS (APCI) 516, 514, 512 (M+H⁺), 512 (100%); NMR δH (d₆-DMSO) 9.16 (1H,t), 7.95-7.60 (3H, m), 7.40 (1H, s), 6.92 (1H, s), 5.14 (1H, d), 4.99(1H, d), 4.92-4.89 (1H, m), 4.36-4.34 (1H, m), 4.08-4.05 (1H, m),3.20-3.14 (2H, m), 2.76-2.72 (1H, m), 2.49-2.18 (2H, m), 1.35-1.30 (2H,m), 1.16-1.09 (2H, m), 0.79 (3H, t).

EXAMPLE 15[1S-(1α,2β,3β,4α)]4-[7-(Butylamino)-5-[4-(trifluoromethyl)phenylthio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid

Prepared according to the method of Example 11 step (b) using theproduct of Example 13 step (b) and 4-(trifluoromethyl)thiophenol.

MS (APCI) 513 (M+H⁺, 100%); NMR δH (d₆-DMSO) 9.14 (1H, t), 7.88 (2H, d),7.81 (2H, d), 5.00-4.91 (1H, m), 4.35-4.33 (1H, m), 4.16-4.10 (1H, m),3.16-3.14 (2H, m), 2.78-2.75 (1H, m), 2.41-2.21 (2H, m), 1.36-1.27 (2H,q), 1.15-1.03 (2H, q), 0.77 (3H, t).

EXAMPLE 16[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-[4-(trifluoromethyl)phenylthio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide

Prepared according to the method, of Example 1 step (h) using theproduct of Example 15.

MS (APCI) 512 (M+H⁺, 100%); NMR δH (d₆-DMSO) 9.14 (1H, t), 7.90-7.79(4H, m), 7.39 (1H, br s), 6.95 (1H, br s), 5.14 (1H, d),4.99 (1H, d),4.93 (1H, m), 4.36-4.34 (1H, m), 4.06 (1H, m), 3.15 (2H, q), 2.76-2.72(1H, m), 2.49-2.19 (2H, m), 1.33-1.29 (2H, m), 1.12-1.05 (2H, m), 0.76(3H, t).

EXAMPLE 17[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(phenylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid

Prepared according to the method of Example 11 step (b) using theproduct of Example 13 step (b) and thiophenol.

MS (APCI) 445 (M+H⁺, 100%); NMR δH (d₆-DMSO) 9.01 (1H, t), 7.62 (2H, m),7.46-7.43 (3H, m), 4.95-4.86 (1H, q), 4.36-4.31 (1H, m), 4.16-4.09 (1H,m), 3.20-3.14 (2H, m), 2.72-2.68 (1H, m), 2.50-2.17 (2H, m), 1.39-1.29(2H, m), 1.19-1.07 (2H, m), 0.79 (3H, t).

EXAMPLE 18[1S-(1α,2β,3β,4α)]4-[7-(Butylamino)-5-(phenylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide

Prepared according to the method of Example 1 step (h) using the productof Example 17.

MS (APCI) 444 (M+H⁺, 100%); NMR δH (d₆-DMSO) 9.03 (1H, t), 7.64-7.44(5H, m), 7.39 (1H, s), 6.95 (1H, m) 5.12 (1H, m), 4.99 (1H, m), 4.89(1H, m), 4.35-4.31 (1H, m), 4.07 (1H, m), 3.17-3.15 (2H, m), 2.75-2.72(1H, m), 2.49-2.16 (2H, m), 1.35-1.34 (2H, m), 1.12 (2H, m), 0.79 (3H,t).

EXAMPLE 19[1S-(1α,2β,3β,4α)]-4-[7-(Cyclopropylamino)-5-(3,4-dichlorophenylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide

(a)[1S-(1α,2β,3β,4α)]-4-[7-(Cyclopropylamino)-5-(propylsulfonyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxalide

Prepared according to the method of Example 11 step (a) using theproduct of Example 3.

MS (APCI) 426 (M+H⁺, 100%).

(b)[1S-(1α,2β,3β,4α)]-4-[7-(Cyclopropylamino)-5-(3,4-dichlorophenylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide

Prepared according to the method of Example 11 step (b) using theproduct of step (a) and 3,4-dichloro-thiophenol.

MS (APCI) 498, 496 (M+H⁺), 496 (100%); NMR δH (d₆-DMSO) 9.28 (1H, d),8.01 (1H, d), 7.81-7.60 (2H, m), 7.40 (1H, s), 6.95 (1H, s), 5.11 (1H,d), 4.98 (1H, d), 4.85 (1H, d), 4.35 (1H, m), 4.07 (1H, q), 2.80 (2H,m), 2.31 (1H, m), 2.11 (1H, m), 0.65 (4H, m).

EXAMPLE 20[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-(2-hydroxyethyl)-cyclopentanecarboxamide

(a)[3aR-(3aα,4α,6α,6aα)]-6-[7-Chloro-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-N-(2-hydroxyethyl)-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide

N,N-Diisopropylethylamine (0.52 ml) was added to a solution ofethanolamine (66 ml), bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate (0.56 g) and the product of Example 1 step (g) (0.45g) in DMF (15 ml). The reaction mixture was stirred at room temperaturefor 1 hour then concentrated. Chromatography (SiO₂, ethyl acetate aseluant) gave the subtitle compound (0.18 g).

MS (APCI) 494 (M+H⁺, 100%).

(b)[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3yl]-2,3-dihydroxy-N-(2-hydroxyethyl)-cyclopentanecarboxamide

Prepared according to the method of Example 1 step (i) using the productof step (a) (55 mg).

MS (APCI) 454 (M+H⁺, 100%); NMR δH (d₆-DMSO) 9.00 (1H, t), 7.94 (1H, t),5.13 (1H, d), 5.00-4.93 (2H, m), 4.68 (1H, t), 4.45-4.11 (1H, m), 4.10(1H, m), 3.53-3.38 (4H, m), 3.17-3.07 (4H, m), 2.78 (1H, m), 2.33-2.24(2H, m), 1.74-1.57 (4H, m), 1.38-1.30 (2H, m), 0.99 (3H, t), 0.91 (3H,t).

EXAMPLE 21[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]yrimidin-3-yl]-2,3-dihydroxy-N-(3-hydroxy-2,2-difluoropropyl)-cyclopentanecarboxamide

(a)[3aR-(3aα,4α,6α,6aα)]-6-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-N-(3-hydroxy-2,2-difluoropropyl)-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide

Prepared according to the method of Example 20 step (a) using2,2-difluoro-1,3-propanediamine and was isolated as a by-product.

MS (APCI) 544 (M+H⁺, 100%).

(b)[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-(3-hydroxy-2,2-difluoropropyl)cyclopentane-carboxamide

Prepared according to the method of Example 1 step (i) using the productof step (a).

MS (APCI) 504 (M+H⁺, 100%); NMR δH (d₆-DMSO) 9.00 (1H, t), 8.32 (1H, t),8.46 (1H, t), 5.18 (1H, d), 5.04 (1H, d), 5.01-4.92 (1H, m), 4.48-4.39(1H, m), 4.14-4.10 (1H, m), 3.64-3.48 (6H, m), 3.12-3.06 (2H, m),2.93-2.83 (1H, m), 2.37-2.10 (3H, m), 1.73-1.57 (4H, m), 1.36-1.30 (2H,m), 0.98 (3H, t), 0.90 (3H, t).

EXAMPLE 22[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-[2-(4-hydroxyphenyl)ethyl]-cyclopentanecarboxamide

(a)[3aR-(3aα,4α,6α,6aα)]-6-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-N-[2-(4-hydroxyphenyl)ethyl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide

Prepared according to the method of Example 20 step (a) using(4-hydroxyphenyl)ethylamine.

MS (APCI) 570 (M+H⁺, 100%).

(b)[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-[2-(4-hydroxyphenyl)ethyl]-cyclopentanecarboxamide

Prepared according to the method of Example 1 step (i) using the productof step (a).

MS (APCI) 530 (M+H⁺, 100%);

NMR δ H (d₆-DMSO) 9.16 (1H, br s), 8.98 (1H, m), 7.97 (1H, m), 6.99 (2H,d), 6.67 (2H, d), 5.12 (1H, d), 4.974.93 (2H, m), 4.42 (1H, m), 4.10(1H, m), 3.48 (2H, m), 3.26-3.19 (2H, m), 3.13-3.07 (2H, m), 2.78-2.70(1H, m), 2.60 (2H, t), 2.31-2.24 (2H, m), 1.74-1.58 (4H, m), 1.38-1.31(2H, m), 0.99 (3H, t), 0.91 (3H, t).

EXAMPLE 23[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-[4-(trifluoromethyl)phenylthio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-(2-hydroxyethyl)-cyclopentanecarboxamide

(a)[3aR-(3aα,4α,6α,6aα)]-6-[7-(Butylamino)-5-(propylsulfonyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxylicacid

Oxone® (5.0 g) was added to a solution of the product of Example 1 step(f) (1.0 g) in acetonitrile (150 ml)/water (10 ml) and the resultingsolution was stirred at room temperature for 3 hours. The solution wasthen diluted with water (100 ml) and extracted with ethyl acetate (3×75ml). The combined extracts were dried and concentrated and the residuepurified (SiO₂, ethyl acetate: methanol, 9:1 as eluant) to give thesubtitle compound (0.79 g).

MS (ESI) 467 (M+H⁺, 100%).

(b)[3aR-(3aα,4α,6α,6aα)]-6-[7-(Butylamino)-5-[4-(trifluoromethyl)phenylthio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxylicacid

Prepared according to the method of Example 11 step (b) using theproduct of step (a) and 4-(trifluoromethyl)thiophenol (0.38 g).

MS (ESI) 553 (M+H⁺, 100%).

(c)[3aR-(3aα,4α,6α,6aα)]-6-[7-(Butylamino)-5-[4-(trifluoromethyl)phenylthio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-N-(2-hydroxyethyl)-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide

Prepared according to the method of Example 20 step (a) using theproduct of step (b).

MS (ESI) 596 (M+H⁺, 100%).

(d)[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-[4-(trifluoromethyl)phenylthio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-(2-hydroxyethyl)-cyclopentanecarboxamide

Prepared according to the method of Example 1 step (i) using the productof step (a).

MS (APCI) 556 (M+H⁺, 100%); NMR δH (d₆-DMSO) 9.14 (1H, t), 7.94 (1H, m),7.89 (1H, m), 5.14 (1H, d), 4.99 (1H, d), 4.93 (1H, m), 4.70 (1H, t),4.38 (1H, m), 4.06 (1H, m), 3.44 (2H, m), 3.18 (4H, m), 2.78 (1H, m),2.33 (1H, m), 2.17 (1H, m), 1.33 (2H, m), 1.09 (2H, m), 0.76 (3H, t).

EXAMPLE 24[1S-(1α,2β,3β,4α)]-N-[1-(Aminocarbonyl)-2-(hydroxy)ethyl]-4-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide

(a)[1S-(1α,2β,3β,4α)]-N-[1-(Aminocarbonyl)-2-(hydroxy)ethyl]-6-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide

Prepared according to the method of example 20, step (a) using theproduct of example 1 step (g) and (2S)-2-amino-3-hydroxy-propanamidehydrochloride.

MS (APCI) 537 (M+H⁺, 100%).

(b)[1S-(1α,2β,3β,4α)]-N-[1-(Aminocarbonyl)-2-(hydroxy)ethyl]-4-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide

A solution of the product of step (a) (0.39 g) in methanol (10 ml)/0.1NHCl(aq) (20 ml) was stirred at room temperature for 2 hours. Thesolution was concentrated and the residue purified (HPLC, Nova-pak® C18column, 0.1% aqueous ammonium acetate:methanol, gradient elution 50:50to 0:100 over 15 minutes) to afford the subtitle compound.

MS (APCI) 497 (M+H⁺, 100%); NMR δH (d₆-DMSO): 9.01 (1H, t), 7.89 (1H,d), 7.28 (2H, d), 5.19 (1H, d), 5.09 (1H, d), 4.97 (1H, m), 4.87 (1H,t), 4.38 (1H, m), 4.27 (1H, m), 4.13 (1H, m), 3.59 (2H, m), 3.50 (2H,m), 3.09 (2H, m), 2.94 (1H, m), 2.34-2.26 (2H, m), (2H, m), 1.72 (2H,s), 1.62 (2H, m), 1.36 (1H, m), 0.99 (3H, t), 0.91 (3H, t).

EXAMPLE 25[1S-[1αa(S*),2β,3β,4α]]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-N-(tetrahydro-3-oxo-isoxazol-4-yl)-2,3-dihydroxy-cyclopentanecarboxamide

Prepared according to the method of Example 20 step (a) using theproduct of Example 2 and D-cycloserine.

Melting point: 209-211° C. (EtOAc);

MS (APCI) 495 (M+H⁺, 100%); NMR δH (d₆-DMSO) 11.53 (1H, s), 9.01 (1H,t), 8.55 (1H, d), 5.16 (1H, d), 5.03 (1H, d), 4.98 (1H, q), 4.78 (1H,m), 4.55 (1H, t), 4.42 (1H, q), 4.11 (1H, m), 3.95 (1H, t), 3.49 (2H,q), 3.10 (2H, m), 2.83 (1H, m), 2.39 (1H, m), 2.27 (1H, m), 1.70 (2H,m), 1.60 (2H, m), 1.34 (2H, m), 0.99 (3H, t), 0.91 (3H, t).

EXAMPLE 26[1S-[1α(R*),2β,3β,4α]]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-(2-oxo-pyrrolidin-3-yl)-cyclopentanecarboxamide

(a)[1S-[1α(R*),2β,3β,4α]]-6-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-tetrahydro-2,2-dimethyl-N-(2-oxo-pyrrolidin-3-yl)-4H-cyclopenta-1,3-dioxole-4-carboxamide

Prepared according to the method of Example 20 step (a) using3-amino-pyrrolidin-2-one hydrochloride (prepared as described in by R.Pellegata, M. Pinza, G. Pifferi, Synthesis 1978, 614).

MS (APCI) 533 (M+H⁺, 100%).

(b)[1S-[1α(R*),2β,3β,4α]]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazoio[4,5-d]pyrimidin-3-yl]-2,3-dhydroxy-N-(2-oxo-pyrrolidin-3-yl)-cyclopentanecarboxamide

A solution of the product from step (a) (0.44 g) in trifluoroacetic acid(25 ml)/dichloromethane (25 ml) was stirred at room temperature for 5hours. The reaction mixture was concentrated and the residue purified bychromatography (HPLC, Nova-pak® C18 column, 0.1% aqueous ammoniumacetate:methanol, gradient elution 50:50 to 0:100 over 15 minutes) toafford the title compound (0.16 g).

MS (APCI) 493 (M+H⁺, 100%); NMR δH (d₆-DMSO) 9.00 (1H, t), 8.25 (1H, d),7.84 (1H, s), 5.05 (1H, br s), 5.21 (1H, br s), 4.98 (1H, m), 4.53 (1H,m), 4.33 (1H, m), 4.09 (1H, m), 3.47 (2H, m), 3.13 (2H, m), 3.08 (2H,m), 2.81 (1H, m), 2.34 (3H, m), 1.78 (1H, m), 1.74 (2H, m), 1.69 (2H,m), 1.60 (2H, m), 0.99 (3H, t), 0.91 (3H, t).

EXAMPLE 27[1S-[1α(R*),2β,3β,4α]]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-(2,3-di-oxo-pyrrolidin-3-yl)-cyclopentanecarboxamide

(a)[1S-[1α(R*),2β,3β,4α]]-6-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-(2,5-di-oxo-pyrrolidin-3-yl)-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide

Prepared according to the method of Example 20 step (a) using3-amino-2,5-pyrrolidinedione (prepared as described by T Polonski, J.Chem. Soc., 1988, 629).

MS (APCI) 547 (M+H⁺, 100%).

[1S-[1α(R*),2β,3β,4α]]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-(2-oxo-pyrrolidin-3-yl)-cyclopentanecarboxamide

Prepared according to the method of example 26 step (b) using theproduct of step (a).

MS (APCI) 507 (M+H⁺, 100%); NMR δH (d₆-DMSO) 11.22 (1H, s), 8.99 (1H,t), 8.63 (1H, d), 5.17 (1H, d), 5.15 (1H, d), 4.99 (1H, m), 4.46 (2H,m), 4.12 (1H, m), 3.49 (2H, m), 3.11 (2H, m), 2.93 (1H, m), 2.77 (1H,m), 2.56 (1H, m), 2.36-2.34 (2H, m), 1.71 (2H, m), 1.64 (2H, m), 1.36(2H, m), 0.98 (3H, t), 0.91 (3H, t).

EXAMPLE 28[1S-[1α(R*),2β,3β,4α]]-N-[(Aminocarbonyl)-methyl]-4-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide

Prepared using the method of Example 20 step (a) using aminoacetamide,followed by the method of Example 26 step (b).

MS (APCI) 467 (M+H⁺, 100%); NMR δH (d₆-DMSO) 8.99 (1H, t), 8.08 (1H, d),7.28 (1H, s), 7.05 (1H, s), 4.98 (1H, m), 4.40 (1H, m), 4.12 (1H, m),3.66 (2H, m), 3.46 (2H, m), 2.85 (1H, m), 2.38-2.27 (2H, m), 1.74 (2H,m), 1.62 (2H, m), 1.36 (2H, m), 0.99 (3H, t), 0.89 (3H, t).

EXAMPLE 29[1S-[1α(R*),2β,3β,4α]]-N-[1-(Aminocarbonyl)-2-(4-hydroxyphenyl)ethyl]4-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide

(a)[1S-[1α(R*),2β,3β,4α]]-N-[1-(Aminocarbonyl)-2-(4-hydroxyphenyl)ethyl]-[6-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide

Prepared according to the method of Example 20 step (a) using(S)-α-amino-4-hydroxy-benzenepropanamide.

MS (APCI) 613 (M+H⁺, 100%).

(b)[1S-[1α(R*),2β,3β,4α]]-N-[1-(Aminocarbonyl)-2-(4-hydroxyphenyl)ethyl]4-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide

Prepared according to the method of Example 26 step (b) using theproduct of step (a).

MS (APCI) 573 (M+H⁺, 100%); NMR δ H (d₆-DMSO) 9.07 (1H, s), 8.98 (1H,t), 8.61 (1H, t), 8.03 (1H, d), 7.39 (1H, s), 7.07 (1H, s), 7.00 (2H,d), 6.58 (2H, d), 4.92 (1H, m), 4.36 (2H, m), 4.10 (1H, m) 3.90 (2H, m),3.50 (2H, m), 3.09 (2H, m), 2.86 (2H, m), 2.66 (1H, m), 2.21 (1H, m),2.06 (1H, m), 1.71 (2H, m), 1.61 (2H, m), 1.36 (2H, m), 0.99 (3H, t),0.91 (3H, t).

EXAMPLE 30[1S-[1α(R*),2β,3β,4α]]-N-[1-(Aminocarbonyl)-2-(hydroxy)ethyl]-4-[7-(butylamino)-5-[4-(trifluoromethyl)phenylthio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide

(a)[3aR-[3aα,4α,4α,6α,6aα]]-6-[7-(butylamino)-5-[4-(trifluoromethyl)phenylthio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxylicacid (0.38 g)

Prepared according to the method of Example 11 (b) using the product ofexample 23, step (a) and 4-(trifluoromethyl)thiophenol.

MS (ESI) 553 (M+H⁺, 100%).

(b)[1S[1α(R*),2β,3β,4α]]-N-[1-(Aminocarbonyl)-2-(hydroxy)ethyl]-4-[7-(butylamino)-5-[4-(trifluoromethyl)phenylthio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide

Prepared according to the method of Example 20 step (a), followed by themethod of Example 26 step (b) using the product of step (a) above.

MS (ESI) 599 (M+H⁺, 100%); NMR δH (d₆-DMSO) 8.73 (1H, s), 7.80 (4H, d),7.56 (1H, d), 6.89 (2H, br s), 4.94 (1H, m), 4.81 (1H, d), 4.72 (1H, d),4.71 (1H, t), 4.42 (1H, m), 4.31 (1H, m), 4.20 (1H, m), 3.69 (2H, m),3.61 (2H, m), 2.99 (1H, m), 2.51-2.25 (2H, m), 1.43 (2H, br s), 1.21(2H, br s), 0.84 (3H, t).

EXAMPLE 31[1S-[1α(1R*,2S*),2β,3β,4α]]-N-[1-(Amino-carbonyl)-2-hydroxy)propyl]-4-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxycyclopentanecarboxamide

(a)[1S-[1α(1R*,2S*),2β,3β,4α]]-N-[1-(Aminocarbonyl)-2-(hydroxy)propyl]-6-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide

Prepared according to the method of Example 20 step (a) using[S-(S*,S*)]-2-amino-3-hydroxy-butanamide.

MS (APCI) 551 (M+H⁺, 100%).

(b)[1S-[1α(1R*,2S*),2β,3β,4α]]-N-[1-(Aminocarbonyl)-2-(hydroxy)propyl]-4-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide

Prepared according to the method of Example 26 step (b) using theproduct of step (a) and purified by chromatography (HPLC, Nova-pak® C18column, 0.1% aqueous ammonium acetate:methanol, gradient elution 30:70to 0:100 over 15 minutes).

MS (APCI) 511 (M+H⁺, 100%). NMR δH (d₆-DMSO) 8.98 (1H, t), 7.68 (1H, d),7.15 (2H, d), 5.18 (1H, d), 5.08 (1H, d), 4.97(1H, m), 4.84 (1H, d),4.40-4.38 (1H, m), 4.17 (1H, d), 4.14 (1H, d), 4.05 (1H, br s), 3.49(2H, q), 3.12-3.08 (2H, m), 3.06-3.00 (1H, m), 2.40 (1H, m), 2.26 (1H,m), 1.69 (2H, m), 1.63 (2H, m), 1.34 (2H, m), 1.02 (3H, sext), 0.99 (3H,t), 0.91 (3H, t).

EXAMPLE 32[1S-[1α,2β,3β,4α]]-N-[2-(Aminocarbonyl)ethyl]-4-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide

(a)[3aR-[3aα,4α,6α,6α]]-N-[2-(Aminocarbonyl)ethyl]-6-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide

Prepared according to the method of example 20 step (a) using3-amino-propanamide.

MS (APCI) 521 (M+H⁺, 100%).

(b)[1S-[1α,2β,3β,4α]]-N-[2-(Aminocarbonyl)ethyl]-4-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide

Prepared according to the method of Example 26 step (b) using theproduct of step (a) above.

MS (APCI) 481 (M+H⁺, 100%); NMR δH (d₆-DMSO) 8.99 (1H, t), 7.97 (1H, t),7.33 (1H, br s), 6.84 (1H, br s), 5.05 (1H, br s), 4.97-4.92 (1H, m),4.434.39 (1H, m), 4.09 (1H, m), 3.52-3.46 (2H, m), 3.28-3.22 (2H, m),3.12-3.07 (2H, m), 2.75-2.72 (1H, m), 2.31-2.20 (4H, m), 1.73-1.55 (4H,m), 1.37-1.31 (2H, m), 1.01-0.88 (6H, m).

EXAMPLE 33[1S-[1α,2β,3β,4α]]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-[2-(methylaminocarbonyl)-ethyl]-cyclopentanecarboxamide

(a)[3aR-[3aα,4α,6α,6aα]]-N-[6-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carbonyl]-β-alanine,1,1-dimethylethyl ester

Prepared according to the method of Example 20 step (a) using β-alanine,1,1-dimethylethyl ester.

MS (APCI) 578 (M+H⁺, 100%).

(b)[1S-[1α,2β,3β,4α]]-N-[4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxycyclopentyl-4-carbonyl]-β-alanine

Prepared according to the method of Example 26 step (b) using theproduct of step (a) above.

MS (APCI) 482 (M+H⁺, 100%).

(c)[1S-[1α,2β,3β,4α]]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-[2-(Methylaminocarbonyl)ethyl]-cyclopentanecarboxamide

Prepared according to the method of example 20 step (a) using theproduct of step (b) and methylamine.

MS (APCI) 495 (M+H⁺, 100%); NMR δH (d₆-DMSO) 9.01 (1H, t), 8.00-7.98(1H, m), 7.81 (1H, m), 5.13 (1H, d), 5.01 (1H, d), 4.96-4.92 (1H, m),4.44-4.40 (1H, m), 4.124.08 (1H, m), 3.48 (2H, q), 3.26 (2H, q);3.13-3.07 (2H, m), 2.76-2.74(1H, m), 2.55 (3H, d), 2.31-2.21 (4H, m),1.70 (2H, sext), 1.62 (2H, m), 1.34 (2H, sext), 0.99 (3H, t), 0.91 (3H,t).

EXAMPLE 34[1S-[1α,2β,3β,4α(1S*,2R*)]]-2,3-Dihydroxy-4-[7-[(2-phenylcyclopropyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxylicacid

a)[3aR-[3aα,4α,6α(1R*,2S*),6aα]]-Tetrahydro-2,2-dimethyl-6-[7-[(2-phenylcyclopropyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-4H-cyclopenta-1,3-dioxole-4-carboxylicacid

A mixture of the product of example 1, step f) (413 mg),(1R-trans)-2-phenylcyclopropylamine,[R-(R*,R*)]-2,3-dihydroxybutanedioate (1:1) (prepared as described by L.A. Mitscher et al., J. Med. Chem. 1986, 29, 2044) (283 mg) andtriethylamine (1.1 ml) in dichloromethane (6 ml) was stirred at roomtemperature for 4 hours. The reaction mixture was concentrated and theresidue purified (SiO₂, ethyl acetate then methanol:ethyl acetate 1:4 aseluant) to afford the subtitle compound (390 mg).

MS (APCI) 511 (M+H⁺, 100%).

b)[1S-[1α,2β,3α,4α(1S*,2R*)]]-2,3-Dihydroxy-4-[7-[(2-phenylcyclopropyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxylicacid

Prepared according to the method of example 1, step i) using the productof step a).

MS (APCI) 471 (M+H⁺, 100%); NMR δH (d₆-DMSO) 9.34 and 8.98 (1H, d),7.31-7.15 (5H, m), 5.18 (2H, br s), 5.02 (1H, m), 4.42 (1H, m), 4.22(1H, m), 3.22 (1H, m), 3.17-2.75 (3H, m), 2.50-2.08 (3H, m), 1.78-1.25(4H, m), 0.81 and 0.99 (3H, t).

EXAMPLE 35[1S-[1α,2β,3β,4α(1S*,2R*)]]-2,3-Dihydroxy-4-[7-[(2-phenylcyclopropyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxamide

a)[3aR-[3aα,4α,6α(1R*,2S*),6aα]]-Tetrahydro-2,2-dimethyl-6-[7-[(2-phenylcyclopropyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-4H-cyclopenta-1,3-dioxole-4-carboxamide

Prepared according to the method of example 1, step h) using the productof example 34, step a).

MS (APCI) 510 (M+H⁺, 100%).

b)[1S-[1α,2β,3β,4α(1S*,2R*)]]-2,3-Dihydroxy-4-[7-(2-phenylcyclopropylamino)]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxamide

Prepared according to the method of example 1, step i) using the productof step a).

MS (APCI) 470 (M+H⁺, 100%);

NMR δH (d₆-DMSO) 9.32 and 8.92 (1H, d), 7.34 (1H, m), 7.29 (2H, m), 7.18(3H, m), 6.89 (1H, s), 5.09 (1H, d), 4.97 (2H, m), 4.42 (1H, m), 4.14(1H, m), 3.21 and 3.88 (1H, m), 2.96 (1H, m), 1.51 and 1.70 (1H, m),1.32 (1H, m), 0.82 and 1.00 (3H, t).

EXAMPLE 36[1S-(1α,2β,3β,4α)]-2,3-Dihydroxy-4-[7-(cyclobutylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxylicacid

a)[3aR-(3aα,4α,6α,6aα)]-6-[7-(Cyclobutylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxylicacid

Prepared according to the method of example 1, step g) using the productof example 1, step f) and cyclobutylamine.

MS (APCI) 449 (M+H⁺, 100%).

b)[1S-(1α,2β,3β,4α)]-4-[7-(Cyclobutylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid

Prepared according to the method of example 1, step i) using the productof step a).

MS (APCI) 409 (M+H⁺, 100%); NMR δH (d₆-DMSO) 0.95-1.01(3H, m), 1.64-1.90(4H, m), 2.11-2.45 (6H, m), 2.75-2.82 (1H, m), 3.03-3.14 (2H, m),4.19-4.22 (1H, m), 4.38-4.45 (1H, m), 4.61-4.69 (1H, m), 4.95-5.03 (1H,m), 9.22 (1H, d).

EXAMPLE 37[1S-(1α,2β,3β,4α)]-4-[7-(Cyclobutylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide

Sieber amide resin (2.0 g) was washed sequentially with a 20% solutionof piperidine in N,N-dimethylformamide (10 ml), N,N-dimethylformamide(DMF) (3×10 ml), dichloromethane (3×10 ml) and diethyl ether (1×10 ml).To the resin was added a solution of the product from example 36 step b)(0.25 g) in dichloromethane (10 ml) and N,N′-diisopropylcarbodiimide(0.13 g). The mixture was shaken for 18 hours then filtered and theresidue washed with dichloromethane and a solution of trifluoroaceticacid in dichloromethane (2%, 4×10 ml). The filtrate was evaporated todryness and the residue purified by chromatography (HPLC, Nova-pak® C18column, 0.1% aqueous ammonium acetate:methanol, gradient elution 40:60to 0:100 over 20 minutes) to afford the title compound (0.095 g).

MS (APCI) 408 (M+H⁺, 100%); NMR δH (d₆-DMSO) 0.96-1.02 (3H, m),1.64-1.76 (4H, m), 2.08-2.39 (6H, m), 2.72-2.80 (1H, m), 3.05-3.15 (1H,m), 4.61-4.69 (1H, m), 4.91-4.99 (2H, m), 5.11 (1H, d), 6.91 (1H,s),7.36 (1H, s), 9.23(1H, d).

EXAMPLE 38[1S-(1α,2β,3β,4α)]-4-[7-(Cyclopropylamino)-5-[[4-(trifluoromethyl)phenyl]thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid.

Prepared according to the method of example 11, step b) using theproduct of example 19, step a) and 4-(trifluoromethyl)thiophenol,followed by the method of example 1 step i).

MS (EI) 497 (M+H³⁰ ); NMR δH (d₆-DMSO) 9.32-9.22 (2H, d), 7.95-7.92 (2H,d), 7.81-7.78 (2H, d), 4.98-4.86 (1H, m) 4.40-4.34 (1H, m), 4.18-4.10(1H, m), 2.76-2.66 (2H, m), 2.5-2.1(2H, t), 0.89-0.50 (4H, m).

EXAMPLE 39[1S-(1α,2β,3β,4α)]-4-[7-(Cyclopropylamino)-5-[[4-(trifluoromethyl)phenyl]thiol-]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide

Prepared according to the method of example 1, step h) using the productof example 38, followed by the method of example 1, step i).

MS (EI) 496 (M+H⁺); NMR δH (d₆-DMSO) 9.25 (1H, d), 7.95-7.92 (2H,d),7.81-7.78 (2H, d), 7.37 (1H, s) 6.94 (1H, s), 5.15 (1H, d), 4.96 (1H,d), 4.98-4.86 (1H, m), 4.40-4.34 (1H, m), 4.13-4.02 (1H, m), 2.76-2.66(2H, m), 2.51-2.10 (2H, t), 0.89-0.50 (4H, m).

EXAMPLE 40[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid

a)[3aR-(3aα,4α,6α,6aα)]-6-[[5-Amino-6-chloro-2-[(3,3,3-trifluoropropyl)thio]-4-pyrimidinyl]amino]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxylicacid

Prepared according to the method of example 1, step e), using4,6-dichloro-5-nitro-2-(3,3,3-trifluoropropylthio)pyrimidine (Preparedas described in WO 9703084).

b)(3aR-(3aα,4α,6α,6aα)]-6-[7-Chloro-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxylicacid

Prepared according to the method of example 1, step f) using the productof step a).

MS (EI, negative ionization) 466 (M−H⁺).

c)[3aR-(3aα,4α,6α,6aα)]-6-[7-(Butylamino)-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxylicacid

Prepared according to the method of example 1, step g) using the productof step b) and butylamine.

MS (APCI) 505 (M+H⁺, 100%).

d)[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid.

Prepared according to the method of example 1, step i) using the productof step c).

MS (APCI) 465 (M+H⁺); NMR δH (d₆-DMSO) 9.10 (1H, t), 4.97-4.93 (1H, m),4.45 (1H, br s), 4.2 (1H, br s), 3.55-3.50 (2H, m), 3.33-3.22 (1H, m),2.80-2.55 (2H, m), 2.35-2.33 (2H, m), 1.71 (2H, s), 1.65-1.52 (2H, m),1.4-1.3 (2H, m), 0.90 (1H t).

EXAMPLE 41[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide

Prepared according to the method of example 1, step h) using the productof example 40, step c), followed by the method of example 1, step i).

MS (EI) 464 (M+H⁺); NMR δH (d₆-DMSO) 9.10 (1H, t), 7.4 (1H s), 6.93 (1Hs), 5.1 (1H, d), 5.00-4.93 (2H, m), 4.12-4.00 (1H, m), 3.56-3.46 (3H,m), 3.35-3.25 (2H, t), 2.82-2.60 (3H, m), 2.4-2.15 (2H, m), 1.7-1.5 (2Hm), 1.4-1.3 (2H m) 0.92-0.88 (3H t).

EXAMPLE 42[1S-(1α,2β,3β,4α)]-2,3-Dihydroxy-4-[7-[(1,4-dimethylpentyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxylicacid

a)[3aR-(3aα,4α,6α,6aα)]-Tetrahydro-2,2-dimethyl-6-[7-[(1,4-dimethylpentyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-4H-cyclopenta-1,3-dioxole-4-carboxylicacid

Prepared according to the method of example 1, step g) using the productof example 1, step f) and 1,4-dimethylpentylamine.

MS (APCI) 493 (M+H⁺, 100%).

b)[1S-(1α,2β,3β,4α)]-2,3-Dihydroxy-4-[7-[(1,4-dimethylpentyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxylicacid

Prepared according to the method of example 1, step i) using the productof step a).

MS (APCI) 493 (M+H⁺, 100%); NMR δH (d₆-DMSO) 0.83-0.86 (6H, m),0.97-1.00 (3H, t), 1.20-1.25 (4H, m), 1.51-1.54 (2H, m), 1.67-1.72 (3H,m), 2.33-2.40 (2H, m), 2.72-2.76 (1H, m), 3.06-3.10 (2H, m), 4.20-4.46(3H, m), 4.95-5.01 (2H, m), 8.73 (1H, d)

EXAMPLE 43[1S-(1α,2β,3β,4α)]-2,3-Dihydroxy-4-[7-[(1,4-dimethylpentyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxamide

a)[3aR-(3aα,4α,6α,6aα)]-Tetrahydro-2,2-dimethyl-6-[7-[(1,4-dimethylpentyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-4H-cyclopenta-1,3-dioxole-4-carboxamide

Prepared according to the method of example 20, step a) using theproduct of example 42, step a) and a solution of ammonia inacetonitrile.

MS (APCI) 479 (M+H⁺, 100%).

b)[1S-(1α,2β,3β,4α)]-2,3-Dihydroxy-4-[7-[(1,4-dimethylpentyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxamide

Prepared according to the method of example 1, step i) using the productof step a).

MS (APCI) 452 (M+H⁺, 100%); NMR δH (d₆-DMSO) 0.82-0.86 (6H, m), 0.98(3H, t), 1.18-1.25 (5H, m), 1.49-1.72 (5H, m), 2.24-2.34 (2H, m),2.75-2.76 (1H, m), 3.06-3.10 (2H, m), 4.11-4.14 (2H, m), 4.93-5.00 (2H,m), 5.13 (1H, d), 6.92 (1H, s), 7.38 (1H, s), 8.82 (1H, d).

EXAMPLE 44[1S-(1α,2β,3β,4α)]-2,3-Dihydroxy-4-[7-[(1-methylbutyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxylicacid

a)[3aR-(3aα,4α,6α,6aα)]-Tetrahydro-2,2-dimethyl-6-[7-[(1-methylbutyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-4H-cyclopenta-1,3-dioxole-4-carboxylicacid

Prepared according to the method of example 1, step g) using the productof example 1, step f) and 1-methylbutylamine.

NMR δH (d₆-DMSO) 0.81-0.90 (5H, m), 1.03-1.11 (7H, m), 1.21-1.44 (8H,m), 1.55 (3H, s), 1.75-1.80 (3H, m), 2.50-2.59 (1H, m), 2.77-2.84 (2H,m), 2.99-3.06 (2H, m), 3.14-3.23 (2H, m), 4.07-4.18 (1H, m), 5.12-5.14(1H, m), 5.64-5.66 (2H, m), 7.76 (1H, d)

b)1S-(1α,2β,3β,4α)]-2,3-Dihydroxy-4-[7-[(1-methylbutyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]yrimidin-3-yl]-cyclopentanecarboxylicacid

Prepared according to the method of example 1, step i) using the productof step a).

MS (APCI) 425 (M+H⁺, 100%); NMR δH (d₆-DMSO) 0.84-0.90 (3H, m), 0.98(3H, t), 1.19-1.35 (5H, m), 1.48-1.52 (2H, m), 1.62-1.73 (4H, m),2.35-2.46 (2H, m), 2.76-2.80 (1H, m), 3.04-3.10 (2H, m), 4.20-4.22 (1H,m), 4.39-4.43 (2H, m), 4.97-5.03 (1H, m), 8.79 (1H, d)

EXAMPLE 45[1S-(1α,2β,3β,4α)]-2,3-Dihydroxy-4-[7-[(1-methylbutyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxamide

a)[3aR-(3aα,4α,6α,6aα)]-Tetrahydro-2,2-dimethyl-6-[7-[(1-methylbutyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-4H-cyclopenta-1,3-dioxole-4-carboxamide

Prepared according to the method of example 20, step a) using theproduct of example 44, step a) and a solution of ammonia inacetonitrile.

MS (APCI) 479 (M+H⁺, 100%).

b)[1S-(1α,2β,3β,4α)]-2,3-Dihydroxy-4-[7-[(1-methylbutyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxamide

Prepared according to the method of example 1, step i) using the productof step a).

MS (APCI) 452 (M+H⁺, 100%); NMR δH (d₆-DMSO) 0.82-0.86 (6H, m), 0.98(3H, t), 1.18-1.25 (5H, m), 1.49-1.72 (5H, m), 2.24-2.34 (2H, m),2.75-2.76 (1H, m), 3.06-3.10 (2H, m), 4.11-4.14 (2H, m), 4.93-5.00 (2H,m), 5.13 (1H, d), 6.92 (1H, s), 7.38 (1H, s), 8.82 (1H, d)

EXAMPLE 46[1S-(1α,2β,3β,4α)]-2,3-Dihydroxy-4-[7-[(1,3-dimethylbutyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5d]pyrimidin-3-yl]-cyclopentanecarboxylicacid

a)[3aR-(3aα,4α,6α,6aα)]-Tetrahydro-2,2-dimethyl-6-[7-[(1,3-dimethylbutyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-4H-cyclopenta-1,3-dioxole-4-carboxylicacid

Prepared according to the method of example 1, step g) using the productof example 1, step f) and 1,3-dimethylbutylamine.

MS (APCI) 479 (M+H⁺, 100%).

b)[1S-(1α,2β,3β,4α)]-2,3-Dihydroxy-4-[7-[(1,3-dimethylbutyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxylicacid

Prepared according to the method of example 1, step i) using the productof step a).

MS (APCI) 439 (M+H⁺, 100%); NMR δH (d₆-DMSO) 0.83-0.91 (6H, m),0.95-1.00 (3H, t), 1.18-1.33 (4H, m), 1.58-1.73 (4H, m), 2.30-2.40 (3H,m), 2.67-2.72 (1H, m), 3.02-3.10 (2H, m), 4.17-4.20 (1H, m), 4.38-4.48(2H, m), 4.94-5.00 (1H, m), 8.78(1H, d).

EXAMPLE 47

[1S-(1α,2β,3β,4α)]-2,3-Dihydroxy-4-[7-[(1,3-dimethylbutyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxamide

Prepared according to the method of example 1, step h) using the productfrom example 46, step b).

MS (APCI) 438 (M+H⁺, 100%); NMR δH (d₆-DMSO) 0.83-0.91 (6H, m), 0.98(3H, t), 1.18-1.34 (4H, m), 1.58-1.74 (4H, m), 2.20-2.36 (2H, m),2.72-2.76 (1H, m), 3.06-3.11 (2H, m), 4.10-4.14 (1H, m), 4.39-4.49 (2H,m), 4.93-4.98 (2H, m), 5.11 (1H, d), 6.91 (1H, s), 7.37 (1H, s), 8.79(1H, d).

EXAMPLE 48[1S-(1α,2β,3β,4α)]-4-[7-(Ethylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid

Prepared according to the method of example 1, step g) using the productof example 1, step f) and ethylamine, followed by the method of example1, step i).

MS (APCI) 381(M−H⁺); NMR δH (d₆-DMSO) 8.98 (1H, t), 5.04-4.99 (1H, m),4.43-4.39 (1H, m), 4.33-4.22 (1H, m), 3.53-3.50 (2H, m), 3.11-3.05 (2H,m), 2.85-2.75 (1H, m), 2.35-2.25(1H, m), 1.80-1.60 (2H, t),1.30-1.15(3H, t),1.00-0.92 (3H, t).

EXAMPLE 49[1S-(1α,2β,3β,4α)]-4-[7-(4-Hydroxybutylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid

a)[3aR-(3aα,4α,6α,6aα)]-Tetrahydro-6-[7-(4-hydroxybutylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxylicacid

Prepared according to the method of example 1, step g) using the productof example 1, step f) and 4-aminobutanol.

MS (APCI) 467 (M+H⁺, 100%).

b)[1S-(1α,2β,3β,4α)]-4-[7-(4-Hydroxybutylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid

Prepared according to the method of example 1, step i) using the productof step a).

MS (APCI) 427 (M+H⁺, 100%); NMR δH (d₆-DMSO) 9.00 (1H, t), 5.19 (2H, brs), 5.00 (1H, q), 4.43-4.39 (2H, m), 4.22 (1H, t), 3.49 (2H, q),3.41(2H, q), 3.13-3.03(2H, m), 2.85-2.78 (1H, m), 2.49-2.31 (2H, m),1.74-1.59 (4H, m), 1.52-1.45 (2H, m), 0.99 (3H, t).

EXAMPLE 50[1S-(1α,2β,3β,4α)]4-[7-(Cyclopentylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid

Prepared according to the method of example 1, step g) using the productof example 1, step f) and cyclopentylamine, followed by the method ofexample 1, step i).

MS (APCI) 423 (M+H, 100%); NMR δH (d₆-DMSO) 9.98 (1H, d), 5.23 (1H, bs),4.97 (2H, q), 4.37-4.21 (1H, m), 3.22-3.01 (2H, m), 2.83 (1H, m),2.50-2.20 (1H, m), 2.10-1.90 (2H, m), 1.83-1.51 (8H, m), 0.98 (3H, t).

EXAMPLE 51

[1S-(1α,2β,3β,4α)]-4-[5-[(4-Bromophenyl)thio]-7-(butylamino)-3H-1,2,3-triazolo[4,5-d]yrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid

Prepared according to the method of example 11, step b) using theproduct of Example 13, step a) and 4-bromothiophenol.

MS (ESI) 525, 523 (M+H⁺, 100%); NMR δH (d₆-DMSO) 9.15-9.11 (1H, t),7.64-7.55 (4H, 2d), 5.24-5.20 (1H, m), 5.01 (1H, m), 4.36-4.33 (1H, m),4.19-4.16 (1H, m), 3.24-3.17 (2H, m), 2.92-2.84 (1H, m), 2.26-2.21 (1H,m), 1.38-1.31 (2H, m), 1.19-1.12 (2H, m), 0.87-0.80 (3H, t).

EXAMPLE 52[1S-(1α,2β,3β,4α)]-4-[7-[(6-Hydroxyhexyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid

Prepared according to the method of example 1, step g) using the productof example 1, step f) and 6-amino-1-hexanol, followed by the method ofexample 1, step i).

MS (APCI) 455 (M+H⁺); NMR δH (d₆-DMSO) 12.44 (1H, s), 9.00 (1H, s),5.20-5.15 (2H, m), 5.05-4.95 (1H, m), 4.55-4.3 (2H, m), 4.25-4.2 (1H,m), 3.50-3.40 (2H, m), 3.40-3.30 (2H, m), 3.15-3.05 (1H, t), 2.85-2.75(1H, t), 2.5-2.35 (1H, m), 1.75-1.6 (2H, m), 1.64-1.52 (2H, n),2.45-2.25 (1H, m), 1.00 (1H, t).

EXAMPLE 53[1S-[1α,2β,3β,4α(trans)]]-2,3-Dihydroxy-4-[5-[[4-(trifluoromethyl)phenyl]thio]-7-[(2-phenylcyclopropyl)amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxylicacid

a)[3aR-(3aα,4α,6α(trans),6aα]]-Tetrahydro-2,2-dimethyl-6-[7-[(2-phenylcyclopropyl)amino]-5-(propylsulfonyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-4H-cyclopenta-1,3-dioxole-4-carboxylicacid

Prepared according to the method of example 11, step a) using theproduct of example 5, step a).

MS (APCI) 543 (M+H⁺, 100%).

b)[3aR-[3aα,4α,6α(trans),6aα]]-Tetrahydro-2,2-dimethyl-6-[5-[[4-(trifluoromethyl)phenyl]thio]-7-[(2-phenylcyclopropyl)amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-4H-cyclopenta-1,3-dioxole-4-carboxylicacid

Prepared according to the method of example 11, step b) using theproduct of step a) and 4-trifluoromethylthiophenol.

MS (APCI) 613 (M+H⁺, 100%).

c)[1S-[1α,2β,3β,4α(trans)]]-2,3-Dihydroxy-4-[5-[[4-(trifluoromethyl)phenyl]thio]-7-[(2-phenylcyclopropyl)amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxylicacid

Prepared according to the method of example 1, step i) using the productof step b).

MS (APCI) 573 (M+H⁺, 100%); NMR δH (d₆-DMSO) 9.44 (1H, d), 7.89-7.59(4H, m), 7.29-7.06 (5H, m), 5.16 (1H, br s), 4.96 (1H, q), 4.34 (1H,brs), 4.15 (1H, t), 3.12-3.00 (1H, m), 2.84-2.77 (1H, m), 2.46-2.40 (1H,m), 2.30-2.20 (2H, m), 1.42-1.35 (1H, m), 1.18-1.07 (1H, m).

EXAMPLE 54[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(cyclopentylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid

Prepared according to the method of example 11, step b) using theproduct of example 13, step a) and cyclopentanethiol, followed by themethod of example 1, step i.

MS (APCI) 437 (M+H⁺, 100%); NMR δH (d₆-DMSO) 8.95 and 8.60 (1H, t), 5.00(1H, m), 4.41 (1H, m), 4.22 (1H, m), 3.98 (1H, m), 3.48 and 3.89 (2H,q), 3.32 (2H, br, s), 2.81 (1H, td), 2.5-2.3 (2H, m), 2.19 (2H, m), 1.63(8H, m), 1.34 (2H, sextet). 0.91 (3H, t)

EXAMPLE 55[1S-(1α,2β,3β,4α)]-2,3-Dihydroxy-4-[7-[(3-methylbutyl)amino]-5-(Propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxylicacid

a)[3aR-(3aα,4α,6α,6aα)]-tetrahydro-2,2-dimethyl-6-[7-[(3-methylbutyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-4H-cyclopenta-1,3-dioxole-4-carboxylicacid

Prepared according to the method of example 1, step g) using the productof example 1, step f) and (3-methylbutyl)amine.

MS (APCI) 465 (M+H⁺, 100%); NMR δH (d₆-DMSO) 7.95 (1H, d), 5.72 (1H, m),5.58 (1H, m), 5.12 (1H, d), 3.36-3.01 (2H, m), 3.02-2.88 (2H, m),2.60-2.46 (1H, m), 1.88-1.78 (2H, m), 1.56 (3H, s), 1.45 (3H), s), 1.10(3H, t), 0.75 (2H, t), 0.38 (2H, br s).

b)(1α,2β,3β,4α)]-2,3-Dihydroxy-4-[7-[(3-Methylbutyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxylicacid

Prepared according to the method of example 1, step i) using the productfrom step a).

MS (APCI) 425 (M+H⁺, 100%); NMR δH (d₆-DMSO) 12.43 (1H, s), 8.73(1H, t),5.16-5.19 (2H, m), 5.00 (1H, q), 4.70-4.30 (1H, m), 4.22 (1H, t),3.49-3.96 (2H, m), 3.06-3.12 (2H, m), 2.79-2.82 (1H, m), 2.46-2.32 (2H,m), 1.62-1.73 (3H, m), 1.48-1.54 (2H, m), 0.99 (3H, t), 0.94 (6H, d).

EXAMPLE 56[1S-[1α,2β,3β,4α(1R*,2S*)]]-2,3-Dihydroxy-4-[7-[(2-phenylcyclopropyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxylicacid

a)[3aR-[3aα,4α,6α(1S*,2R*),6aα]]-Tetrahydro-2,2-dimethyl-6-[7-[(2-phenylcyclopropyl)amino)]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-4H-cyclopenta-1,3-dioxole-4-carboxylicacid

A mixture of the product of example 1, step f) (1.0 g),(1S-trans)-2-phenylcyclopropylamine[R-(R*,R*)]-2,3-dihydroxybutanedioate(1:1) (prepared as described by L. A. Mitscher et al., J. Med. Chem.1986, 29, 2044) (680 mg) and diisopropylethylamine (1.68 ml) indichloromethane (30 ml) was stirred at room temperature for 3 days. Thereaction mixture was concentrated and the residue purified (SiO₂,dichloromethane:methanol:acetic acid 1650:150:1 as eluant) to afford thesubtitle compound (862 mg).

MS (APCI) 511 (M+H⁺, 100%).

b)[1S-[1α,2β,3β,4α(1R*,2S*)]]-2,3-Dihydroxy-4-[7-[(2-phenylcyclopropyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxylicacid

Prepared according to the method of example 1, step i) using the productof step a).

MS (APCI) 471 (M+H⁺, 100%); NMR δH (d₆-DMSO) 12.42 (1H, br s), 9.34 and8.98 (1H, d), 7.31-7.15 (5H, m), 5.02 (1H, m), 4.40 (1H, m), 4.22 (1H,m), 3.19 (1H, m), 3.16-2.75 (3H, m), 2.50-2.08 (3H, m), 1.75-1.22 (4H,m), 0.82 and 0.98 (3H, t)

EXAMPLE 57[1S-[1α(R*),2β,3β,4α]]-N-(3-Amino-3-oxo-2-propyl)-4-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentylcarboxamide

a)[3aR-[3aα,4α(S*),6α,6aα]]-N-(3-Amino-3-oxo-2-propyl)-6-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide

Prepared according to the method of example 20, step a), using theproduct of example 1, step g) and (2S)-2-amino-propanamide,hydrobromide.

MS (APCI) 521 (M+H⁺, 100%).

b)[1S-[1α(R*),2β,3β,4α]]-N-(3-Amino-3-oxo-2-propyl)-4-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentylcarboxamide.

Prepared according to the method of example 1, step i) using the productof step a).

NMR δH (d₆-DMSO) 8.99 (1H, t), 8.04 (1H, d), 7.31 (1H, s), 7.03 (1H, s),4.97 (1H, q), 4.40 (1H, t), 4.25 (1H, m), 4.12 (1H, t), 3.50 (2H, q),3.09 (2H, m), 2.87 (1H, m), 2.27 (2H, m), 1.69 (2H, m), 1.60 (2H, m),1.36 (2H, m), 1.19 (2H, d), 0.99 (3H, t), 0.91 (3H, t).

EXAMPLE 58[1S-[1α(R*),2β,3β,4α]]-3-[7-(Butylamnino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-[3-hydroxy-1-(methylamino)-1-oxo-2-propyl]-cyclopentanecarboxamide

Prepared according to the method of example 20, step a) using theproduct of example 1, step g) and(2S)-2-amino-3-hydroxy-N-methyl-propanamide, hydrochloride (prepared asdescribed by Zahn, H. Reinert, G , Hoppe-Seyler, Z-Physiol.Chem, 1968,349, 608) followed by the method of example 1, step i).

NMR δH (d₆-DMSO) 8.98 (1H, t), 7.93 (1H, d), 7.80 (1H, d), 5.17 (1H, d),5.07 (1H, d), 4.97 (1H, m), 4.88 (1H, t), 4.45 (1H, m), 4.28 (1H, m),4.17 (1H, m), 3.53 (4H, m), 3.10 (2H, m), 2.93 (1H, m), 2.61 (3H, d),2.24-2.37 (2H, m), 1.73 (2H, m), 1.64 (2H, m), 1.64 (2H, m), 1.35 (2H,m), 0.98 (3H, t), 0.90 (3H, t).

EXAMPLE 59[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-[3-(dimethylamino)-3-oxo-propyl]-cyclopentanecarboxamide

a)[3aR-(3aα,4α,6α,6aα)]-N-[6-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ylcarbonyl]-β-alanine,1,1-dimethylethyl ester

N,N-Diisopropylethylamine (0.37 ml) was added to a solution ofβ-alanine, 1,1-dimethylethyl ester, hydrochloride (0.20 g),benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate(0.49 g) and the product of example 1, step g) (0.45 g) in THF (10 ml).The reaction mixture was stirred at room temperature for 3 hours thenconcentrated. The residue was taken into ethyl acetate and washed withsaturated aqueous sodium bicarbonate solution then dried andconcentrated. Purification (SiO₂, dichloromethane:methanol 197:3 aseluant) gave the subtitle compound (0.45 g).

MS (APCI) 578 (M+H⁺, 100%).

b)[1S-(1α,2β,3β,4α)]-N-[[4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopent-1-yl]carbonyl]-β-alanine

Prepared according to the method of example 1, step i) using the productof step a).

MS (APCI) 482 (M+H⁺, 100%).

c)[1S-(1α,2β,3β,4α)]4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-[3-(dimethylamino)-3-oxo-propyl]-cyclopentanecarboxamide

Prepared according to the method of step a) using the product of step b)and dimethylamine hydrochloride.

MS (FAB) 509 (M+H⁺, 100%); NMR δH (d₆-DMSO) 0.91 (3H, t), 0.99 (3H, t),1.31-1.37 (2H, m), 1.58-1.73 (4H, m), 2.24-2.31 (2H, m), 2.69-2.73 (2H,m), 2.74-2.76 (1H, m), 2.81 (3H, s), 2.94 (3H, s), 3.07-3.12 (2H, m),3.25-3.33 (2H, m), 3.47-3.50 (2H, m), 4.084.11 (1H, m), 4.40-4.42 (1H,m), 4.93-5.20 (3H, m), 7.93 (1H, t), 8.99 (1H, t).

EXAMPLE 60[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-[2-(dimethylamino)-2-oxo-ethyl)-cyclopentanecarboxamide

a)[3aR-(3aα,4α,6α,6aα)]-N-[[6-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4N-cyclopenta-1,3-dioxol-4-yl]carbonyl]-glycine,1,1-dimethylethyl ester

Prepared according to the method of example 59, step a) using theproduct of example 1, step g) and glycine, 1,1-dimethylethyl ester,hydrochloride.

MS (APCI) 564 (M+H⁺, 100%).

b)[1S-(1α,2β,3β,4α)]-N-[[4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopent-1-yl]carbonyl]-glycine

Prepared according to the method of example 1, step i) using the productof step a).

MS (APCI) 468 (M+H⁺, 100%).

c)[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-[2-(dimethylamino)-2-oxo-ethyl)-cyclopentanecarboxamide

Prepared according to the method of example 59, step a) using theproduct of step b) and dimethylamine hydrochloride.

MS (FAB) 495 (M+H⁺, 100%); NMR δH (d₆-DMSO) 0.90 (3H, t), 1.01 (3H, t),1.30-1.38 (2H, m), 1.57-1.73 (4H, m), 2.23-2.38 (2H, m), 2.83 (3H, s),2.86-2.92 (1H, m), 2.95 (3H, s), 3.06-3.12 (2H, m), 3.46-3.52 (2H, m),3.94-3.96 (2H, m), 4.13 (1H, m), 4.95-5.14 (3H, m), 7.98 (1H, t), 8.98(1H, t).

EXAMPLE 61[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-[3-oxo-3-[(phenylmethyl)amino]-propyl]-cyclopentanecarboxamide

Prepared according to the method of example 59, step a) using theproduct of example 59, step b) and benzylamine.

MS (APCI) 571 (M+H⁺, 100%); NMR δH (d₆-DMSO) 0.91 (3H, t), 0.99 (3H, t),1.32-1.37 (2H, m), 1.58-1.73 (4H, m), 2.15-2.34 (4H, m), 2.72-2.78 (1H,m), 3.07-3.12 (2H, m), 3.49-3.50 (2H, m), 4.11-4.12 (1H, m), 4.24-4.28(2H, m), 4.42-4.44 (1H, m), 4.93-4.98 (2H, m), 5.12-5.14(1H, m),7.19-7.29 (5H, m), 8.01 (1H, t), 8.39 (1H, t), 8.99 (1H, t).

EXAMPLE 62[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-[2-(methylamino)-2-oxo-ethyl)-cyclopentanecarboxamide

Prepared according to the method of example 59, step a) using theproduct of example 60 step b) and methylamine hydrochloride.

MS (APCI) 481 (M+H⁺, 100%); NMR δH (d₆-DMSO) 0.88-1.00 (6H, m),1.30-1.38 (2H, m), 1.57-1.73 (4H, m), 2.26-2.38 (3H, m), 2.59 (2H, d),2.86-2.87 (1H, m), 3.06-3.12 (2H, m), 3.46-3.52 (2H, m), 3.68 (2H, d),4.13 (1H, t), 4.38-4.42 (1H, m), 4.94-5.00 (2H, m), 7.75 (2H, d), 8.14(1H, t), 8.98 (1H, t).

EXAMPLE 63[1S-(1α(R*),2β,3β,4α)]-N-[4-Amino-1-(aminocarbonyl)-4-oxo-butyl]4-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3yl]-2,3-dihydroxy-cyclopentanecarboxamide

a)[3aR-(3aα,4α(S*),6α,6aα)]-N-[4-Amino-1-(aminocarbonyl)-4-oxo-butyl]-6-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole]-cyclopentanecarboxamide.

Sieber amide resin (1.0 g) was washed sequentially with a solution ofpiperidine in dimethylformamide (20%; 10 ml), N,N-dimethylformamide(DMF) (3×10 ml) and dichloromethane (3×10 ml). To the resin was added asolution of N-α-(9-fluorenylmethoxycarbonyl)-L-glutamine (0.37 g) in DMF(10 ml), followed by N,N′-diisopropylcarbodiimide (0.16 ml) and themixture stirred for 4 hours. The mixture was filtered and the residuewashed sequentially with dichloromethane (3×10 ml), DMF (3×10 ml), asolution of piperidine in DMF (20%, 10 ml), DMF (3×10 ml) anddichloromethane (3×10 ml). The resin was suspended in dichloromethane (5ml) and treated with the product of example 1, step g) (0.30 g) andN,N′-diisopropylcarbodiimide (0.16 ml). After stirring for 16 hours theresin was washed with dichloromethane (3×10 ml) then trifluoroaceticacid in dichloromethane (2%, 3×10 ml). The combined washings wereconcentrated and the residue purified by chromatography (HPLC, Nova-pak®C18 column, 0.1% aqueous ammonium acetate:acetonitrile, gradient elution40:60 to 60:40 over 12 minutes) to afford the subtitle compound (0.05g).

MS (APCI) 578 (M+H⁺, 100%)

b)[1S-(1α(R*),2β,3β,4α)]-N-[4-Amino-1-(aminocarbonyl)-4-oxo-butyl]-4-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3yl]-2,3-dihydroxy-cyclopentanecarboxamide.

Prepared according to the method of example 1, step i) using the productof step a).

NMR δH (d₆-DMSO) 9.00 (1H, t), 8.03 (1H, d), 7.34 (1H, s), 7.25 (1H, s),7.08 (1H, s), 6.73 (1H, s), 4.97 (1H, q), 4.40 (1H, t), 4.14 (1H, t),3.51 (2H, q), 3.10 (2H, m), 2.91 (1H, m), 2.38 (1H, m), 2.21 (1H, m),2.06 (2H, t), 1.88 (1H, m), 1.69 (3H, m), 1.60 (2H, m), 1.36 (2H, m),0.99 (3H, t), 0.91 (3H, t).

EXAMPLE 64[1S-(1α,2β,3β,4α)]-N-[4-Amino-1-[(methylamino)carbonyl]-4-oxo-butyl]4-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide

a)(2S)-5-Amino-N-methyl-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-oxo-propanamide

Prepared according to the method of example 20, step a) usingN-2-[(1,1-dimethylethoxy)carbonyl]-L-glutamine and methylaminehydrochloride.

MS (APCI) 258 (M−H⁺),184 (100%)

b) (4S)-4-Amino-5-(methylamino)-5-oxo-pentanamide hydrochloride

A solution of the product from step a) (0.52 g) in 4M hydrogenchloride/1,4-dioxane (10 ml) was stirred at room temperature for 2hours. The reaction mixture was concentrated and the residue purified byreverse phase chromatography (Preparative C18 125 Å bulk packingmaterial, water: methanol, gradient elution 0:100 to 100:0) to affordthe sub-title compound (0.36 g).

NMR δH (d₆-DMSO) 1.82-2.01 (2H, m), 2.14-2.19 (2H, m), 2.65 (3H, d),3.74-3.76 (1H, m), 6.90 (1H , s), 7.48 (1H, s), 8.34 (1H, s), 8.60 (1H,q).

c)[3aR-(3aα,4α(S*),6α,6aα)]-N-[4-Amino-1-(1-methylamino)carbonyl-4-oxobutyl]-6-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolopyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl-carboxamide

Prepared according to the method of example 20, step a) using theproduct of step b) and the product of example 1, step g).

MS (APCI) 592 (M+H⁺, 100%).

d)[1S-(1α,2β,3β,4α)]-N-[4-Amino-1-[(methylamino)carbonyl]-4-oxo-butyl]4-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamnide

Prepared according to the method of example 1, step i) using the productof step c).

MS (APCI) 552 (M+H⁺, 100%); NMR δH (d₆-DMSO) 0.91 (3H,t), 0.98 (3H,t),1.36 (2H,sex), 1.62 (2H,quin), 1.69 (2H, sex), 1.66-1.74 (1H, m),1.80-1.95 (1H, m), 2.03 (2H, t), 2.15-2.25 (1H, m), 2.30-2.40 (1H, m),2.60 (3H, d), 2.89-2.90 (1H, m), 3.06-3.18 2H, m), 3. (2H, q), 4.12-4.16(1H, m), 4.19-4.21 (1H, m), 4.39-4.42 (1H, m), 4.90-5.00 (1H, m), 5.03(1H, d), 5.15 (1H, d), 6.71 (1H, s), 7.23 (1H, s), 7.85 (1H, q), 8.07(1H, d), 8.99 (1H, t).

EXAMPLE 65[1S-(1α(R*),2β,3β,4α)]-N-[1-(Aminocarbonyl)-3-hydroxy-propyl)-4-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide

Prepared according to the method of example 59, step a) using theproduct of example 2 and (2S)-2-amino-4-hydroxy-butanamide (prepared asdescribed by R. M. Khomutov et al, Chem. Abs., 58, 13944)

MS (APCI) 511 (M+H⁺, 100%); NMR δH (d₆-DMSO) 8.99 (1H, t), 8.02 (1H, d),7.29 (1H, s), 7.05 (1H, s), 5.16 (1H, d), 5.03 (1H, d), 5.00-4.92 (1H,m), 4.46 (1H, t), 4.43-4.37 (1H, m), 4.33-4.26 (1H, m), 4.18-4.12 (1H,m), 3.50 (2H, q), 3.43-3.37 (2H, m), 3.20-3.02 (2H, m), 2.94-2.87 (1H,m), 2.42-2.32 (1H, m), 2.28-2.15 (1H, m), 1.90-1.79 (1H, m), 1.77-1.55(5H, m), 1.44-1.29 (2H, m), 0.99 (3H, t), 0.91 (3H, t).

EXAMPLE 66[1S-(1α(R*),2β,3β,4α)]-N-[1-(Aminocarbonyl)-2-hydroxy-ethyl)-2,3-dihydroxy-4-[7-[(4-phenylbutyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxamide

a)[3aR-(3aα,4α,6α,6aα)]-Tetrahydro-2,2-dimethyl-6-[7-[(4-phenylbutyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]4H-cyclopenta-1,3-dioxole-4-carboxylicacid

Prepared according to the method of example 1, step g) using the productof example 1, step f) and 4-phenylbutylamine.

MS (APCI) 527 (M+H⁺, 100%)

b)[3aR-(3aα,4α,6α(S*),6aα)]-N-[1-(Aminocarbonyl)-2-hydroxy-ethyl)-tetrahydro-2,2-dhnethyl-6-[7-[(4-phenylbutyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-4H-cyclopenta-1,3-dioxole-4-carboxamide

Prepared according to the method of example 59, step a) using theproduct of step a) and (2S)-2-amino-3-hydroxy-propanamide,hydrochloride.

MS (APCI) 613 (M+H⁺, 100%)

c) [1S-(1α(R*),2β,3β,4α)]-N-[1-(Aminocarbonyl)-2-hydroxy-ethyl)-2,3-dihydroxy-4-[7-[(4-phenylbutyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxamide

Prepared according to the method of example 1, step (i) using theproduct from step (b).

MS (APCI) 573 (M+H⁺, 100%); NMR δH (d₆-DMSO) 9.01 (1H, t), 7.88 (1H, d),7.27-7.13 (7H, m), 5.17 (1H, d), 5.07 (1H, d), 4.97-4.95 (1H, m),4.87-4.84 (1H, m), 4.39-4.37 (1H, m), 4.26-4.24 (1H, m), 4.15-4.13 (1H,m), 3.60-3.51 (4H, m), 3.10-3.05 (2H, m), 2.93-2.29 (1H, m), 2.61 (2H,m), 2.34 (1H, m), 2.25 (1H, m), 1.71-1.63 (6H, m), 0.98 (3H, t).

EXAMPLE 671S-[1α,2β,3β,4α(1S*,2R*)]-N-[(Aminocarbonyl)methyl]-2,3-dihydroxy-4-[7-[(2-phenylcyclopropyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxamide

a)[3aR-(3aα,4α,6α(1R*,2S*),6aα]-N-[(Aminocarbonyl)methyl]-tetrahydro-2,2-dimethyl-6-[7-[2-(phenylcyclopropyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-4H-cyclopenta-1,3-dioxole-4-carboxamide

Prepared according to the method of example 59, step a) using theproduct of example 34, step a) and glycinamide hydrochloride.

MS (APCI) 567 (M+H⁺)

b)1S-[1α,2β,3β,4α(1S*,2R*)]-N-[(Aminocarbonyl)methyl]-2,3-dihydroxy-4-[7-[(2-phenylcyclopropyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxamide

Prepared according to the method of example 26, step b) using theproduct of step a).

MS (APCI) 527 (M+H⁺); NMR δH (d₆-DMSO) 9.31 (1H, d), 8.04 (1H, br t),7.26-7.11 (6H, m), 7.00 (1H, br s), 5.12 (1H, d), 5.00 (1H, d), 4.94(1H, m), 4.37 (1H, m), 4.10 (1H, m), 3.63 (2H, m), 3.16 (1H, m), 2.91(1H, m), 2.81 (2H, m), 2.33-2.18(2H, m), 2.08 (1H, m), 1.47 (1H, m),1.28 (1H, m), 0.76 (3H, t).

EXAMPLE 68[1S-(1α(R*),2β,3β,4α)]-N-[(1-Aminocarbonyl)-4-(methylamino)-4-oxo-butyl]-4-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide

a) (2S)-2-Amino-5-(methylamino)-5-oxo-pentanamide

N,N-Diisopropylethylamine (2.0 ml) was added to a solution of(4S)-5-amino-4-[[(1,1-dimethylethoxy)carbonyl]amino]-5-oxo-pentanoicacid (0.49 g), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate(1.20 g) and methylamine (0.16 g) in acetonitrile (20 ml). The reactionmixture was stirred at room temperature for 2 hours then concentrated.The residue was taken into 4M HCl in 1,4-dioxane (20 ml), stirred for 4hours then concentrated. Purification (Preparative C18 125 Å bulkpacking material, water:methanol, gradient elution 0:100 to 100:0) gavethe sub-title compound (0.48 g).

NMR δH (d₆-DMSO) 8.24 (2H, br s), 8.00-7.98 (1H, m), 7.95 (1H, be s),7.58 (1H, br s), 3.74 (1H, br s), 2.56 (3H, d), 2.26-2.12 (2H, m),2.10-1.92 (2H, m).

b)[3αR-[3aα,4α(S*),6α,6aα]]-N-[1-(Aminocarbonyl)-4-(methylamino)-4-oxobutyl]-6-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole4-carboxamide

Prepared according to the method of example 20, step a) using theproduct of step a) and the product of example 1, step g).

MS (APCI) 593 (M+H⁺, 100%)

c)[1S-(1α(R*),2β,3β,4α)]-N-[(1-Aminocarbonyl)-4-(methylamino)-4-oxo-butyl]4-[7-(butylamlino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3yl]-2,3-dihydroxy-cyclopentanecarboxamide

Prepared according to the method of example 1, step i) using the productfrom step b).

MS (APCI) 552 (M+H⁺, 100%); NMR δH (d₆-DMSO) 8.99 (1H, t), 8.02 (1H, d),7.69 (1H, q), 7.33 (1H, s), 7.08 (1H, s), 5.15 (1H, br s), 5.03 (1H, brs), 4.97-4.94 (1H, m), 4.40 (1H, br s), 4.21-4.16 (1H, br s), 4.16-4.14(1H, br s), 3.49 (2H, q), 3.13-3.06 (2H, m), 2.91-2.89 (1H, m), 2.53(3H, d), 2.38-2.35 (1H, m), 2.23 (1H, m), 2.06 (2H, t), 1.90-1.89 (1H,m), 1.77-1.66 (1H, m), 1.74 (2H, sextuplet), 1.63 (2H, quint), 1.34 (2H,sextuplet), 0.99 (3H, t), 0.91 (3H, t).

EXAMPLE 69[1S-(1α,2β,3β,4α)]-2,3-Dihydroxy-4-[7-[(4-phenylbutyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxylicacid

Prepared according to the method of example 1, step i) using the productof example 66, step a).

MS (APCI) 487 (M+H⁺); NMR δH (d₆-DMSO) 9.00 (1H, t), 7.28-7.12 (5H, m),5.18-5.14 (1H, m), 5.04-4.95 (1H, m), 4.43-4.37 (1H, m), 4.22-4.21 (1H,m), 3.53-3.51 (1H, m), 3.12-2.99 (2H, m), 2.85-2.78 (1H, m), 2.61 (2H,m), 2.49-2.27 (2H, m), 1.74-1.63 (6H, m), 0.98 (3H, m), 0.98 (3H, t).

EXAMPLE 70[1S-(1α,2β,3β,4α)]-2,3-Dihydroxy-4-[7-[(1-phenylcyclopropyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxylicacid

a)[3aR-(3aα,4α,6α,6aα)]-Tetrahydro-2,2-dimethyl-6-[7-[(1-phenylcyclopropyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-4H-cyclopenta-1,3-dioxole-4-carboxylicacid

Prepared according to the method of example 1 step g) using the productof example 1, step f) and 1-phenylcyclopropylamine.

MS (APCI) 511 (M+H⁺, 100%)

b)[1S-(1α,2β,3β,4α)]-2,3-Dihydroxy-4-[7-[(1-phenylcyclopropyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxylicacid

Prepared according to the method of example 1, step i) using the productof step a).

MS (APCI) 471 (M+H⁺); NMR δH (d₆-DMSO) 9.79 (1H, s), 7.27-7.13 (5H, m),5.18 (2H, br s), 5.00 (1H, q), 4.40 (1H, br s), 4.22-4.20 (1H, m),2.88-2.80 (3H, m), 2.49-2.30 (2H, m), 1.47-1.35 (6H, m), 0.77 (3H, t).

EXAMPLE 71[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-(2,3-dihydroxypropyl)-cyclopentanecarboxamide

Prepared according to the method of example 59, step a) using theproduct of example 2 and 3-amino-1,2-propanediol.

MS (APCI) 484 (M+H⁺, 100%); NMR δH (d₆-DMSO) 8.98 and 8.60 (1H, t), 7.89(1H, m), 5.12 (1H, d), 5.00-4.90 (2H, m), 4.76 and 4.75 (1H, d), 4.52(1H, t), 4.42 (1H, m), 4.12 (1H, m), 3.49 and 3.90 (3H, m), 3.32-3.19(3H, m), 3.18-2.98 (3H, m), 2.83 (1H, m), 2.40-2.18 (2H, m), 1.71 (2H,sextet), 1.63 (2H, quintet), 1.35 (2H, sextet), 0.99 (3H, t), 0.91 (3H,t).

EXAMPLE 72[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-[2-hydroxy-2-(4-hydroxyphenyl)-ethyl]-cyclopentanecarboxamide

Prepared according to the method of example 59, step a) using theproduct of example 2 and α-(aminomethyl)-4-hydroxybenzylalcoholhydrochloride.

NMR δH (d₆-DMSO) 9.24 (1H, s), 8.98 (1H, t), 7.91 (1H, m), 7.12 (2H, t),6.70 (2H, m), 5.27 (1H, m), 5.12 (1H, d), 4.51 (1H, m), 4.42 (1H, m),4.10 (1H, m), 3.51 (2H, q), 3.10 (3H, m), 2.82 (1H, m), 2.30 (1H, m),2.20 (1H, m), 1.72 (4H, m), 1.36 (2H, m), 0.99 (3H, t), 0.91 (3H, t).

EXAMPLE 73[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-[2-hydroxy-2-(3-hydroxyphenyl)-ethyl]-cyclopentanecarboxamide

Prepared according to the method of example 59, step a) using theproduct of example 2 and α-(aminomethyl)-3-hydroxybenzylalcoholhydrochloride.

NMR δH (d₆-DMSO) 9.27 (1H, s), 8.98 (1H, t), 7.97 (1H, t), 7.08 (1H, m),6.72 (2, m), 6.62 (1H, d), 5.38 (1H, m), 5.12 (1H, d), 4.95 (2H, m),4.52 (1H, m),.4.45 (1H, m), 4.12 (1H, m), 3.50 (2H, q), 3.30 (1H, m),3.09 (3H, m), 2.82 (1H, m), 1.71 (2H, m), 1.60 (2H, m), 1.35 (2H, m),0.98 (3H, t), 0.90 (3H, t).

EXAMPLE 74[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-[(4-hydroxy-3-methoxyphenyl)-methyl]-cyclopentanecarboxamide

Prepared according to the method of example 59, step a) using theproduct of example 2 and 4-hydroxy-3-methoxybenzylamine hydrochloride.

NMR δH (d₆-DMSO) 8.81 (1H, s), 8.98 (1H, t), 8.33 (1H, t), 6.83 (1H, d),6.68 (2H, m), 5.16 (1H, d), 5.00 (1H, d), 4.98 (1H, t), 4.45 (1H, m),4.20 (3H, m), 3.72 (3H, s), 3.50 (2H, q), 3.09 (2H, m), 2.84 (1H, m),2.32 (2H, m), 1.70 (2H, m), 1.59 (2H, m), 1.35 (2H, m), 0.97 (3H, t),0.90 (3H, t).

EXAMPLE 75[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-[(4-hydroxyphenyl)-methyl]-cyclopentanecarboxamide.

a) 4-Hydroxybenzylamine hydrobromide

4-Methoxybenzylamine (1.00 ml) in 48% HBr aq (10 ml) and heated atreflux for 10 hours. The cooled reaction mixture was filtered to givethe sub-title compound (2.25 g).

NMR δH (d₆-DMSO) 9.59 (1H, s), 8.01 (3H, br s), 7.27 (2H, d), 6.80 (2H,d), 3.91 (3H, d).

b)[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-[(4-hydroxyphenyl)-methyl]-cyclopentanecarboxamide.

Prepared according to the method of example 59, step a) using theproduct of example 2 and product of step a).

NMR δH (d₆-DMSO) 9.26 (1H, s), 8.99 (1H, t), 8.32 (1H, t), 7.08 (2H, d),6.70 (2H, d), 5.14 (1H, d), 5.00 (1H, d), 4.95 (1H, m), 4.46 (1H, m),4.19 (3H, m), 3.51 (2H, q), 3.10 (1H, m), 2.83 (1H, m), 2.31 (2H, m),1.69 (2H, m), 1.60 (2H, m), 1.36 (2H, m), 0.99 (3H, t), 0.91 (3H, t).

EXAMPLE 76[1S-[1α,2β,3β,4α(1R*,2S*)]]-2,3-Dihydroxy-N-(2-hydroxyethyl)-4-[7-[(2-phenylcyclopropyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxamide

a)[3aR-[3aα,4α,6α(1S*,2R*),6aα]]-Tetrahydro-N-(2-hydroxyethyl)-2,2-dimethyl-6-[7-[(2-phenylcyclopropyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-4H-cyclopenta-1,3-dioxole-4-carboxamide

Prepared according to the method of example 20, step a) using theproduct of example 56, step a).

MS (APCI) 554 (M+H⁺, 100%).

b)[1S-[1α,2β,3β,4α(1R*,2S*)]]-2,3-Dihydroxy-N-(2-hydroxyethyl)-4-[7-[(2-phenylcyclopropyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxamide

Prepared according to the method of example 1, step i) using the productof step a).

MS (APCI) 514 (M+H⁺, 100%); NMR δH (d₆-DMSO) 9.35 and 8.96 (1H, m), 8.02(1H, t), 7.31-7.15 (5H, m), 5.29 (2H, br s), 4.96 (1H, m), 4.78 (1H, brs), 4.41 (1H, m), 4.10 (1H, m), 3.42 (2H, m), 3.25-2.74 and 3.82 (6H,m), 2.40-2.10 (3H, m), 1.80-1.28 (4H, m), 0.81 and 0.99 (3H, t).

EXAMPLE 77[1S-[1α,2β,3β,4α(1S*,2R*)]]-2,3-Dihydroxy-N-(2-hydroxyethyl)-4-[7-[(2-phenylcyclopropyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxamide

a)[3aR-[3aα,4α,6α(1R*,2S*),6aα]]-Tetrahydro-N-(2-hydroxyethyl)-2,2-dimethyl-6-[7-[(2-phenylcyclopropyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-4H-cyclopenta-1,3-dioxole-4-carboxamide

Prepared according to the method of example 20, step a) using theproduct of example 34, step a).

MS (APCI) 554 (M+H⁺, 100%).

b)[1S-[1α,2β,3β,4α(1S*,2R*)]]-2,3-Dihydroxy-N-(2-hydroxyethyl)-4-[7-(2-phenylcyclopropylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxamide

Prepared according to the method of example 1, step i) using the productof step a).

MS (APCI) 514 (M+H⁺, 100%); NMR δH (d₆-DMSO) 9.35 and 8.95 (1H, d), 7.92(1H, t), 7.31-7.15 (5H, m), 5.12 (1H, d) 5.00-4.92 (2H, m), 4.67 (1H,t), 4.43 (1H, m), 4.10 (1H, q), 3.41 (2H, q), 3.21-3.12 and 3.85 (3H,m), 3.01-2.72 (3H, m), 2.40-2.10 (3H, m), 1.77-1.42 (3H, m), 1.32 (1H,m), 0.81 and 0.99 (3H, t)

EXAMPLE 78[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-[(2-hydroxy-5-nitrophenyl)methyl]-cyclopentanecarboxamide

a)[3aR-(3aα,4α,6α,6aα)]-6-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-]pyrimidin-3yl]-tetrahydro-N-[(2-hydroxy-5-nitrophenyl)methyl]-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide

Prepared according to the method of example 59, step a) using theproduct of example 1, step g) and 2-(aminomethyl)-4-nitrophenol.

MS (APCI) 601 (M+H⁺, 100%).

b)[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-[(2-hydroxy-5-nitrophenyl)methyl]-cyclopentanecarboxamide

Prepared according to the method of example 1 step i) using the productof step a).

MS (APCI) 561 (M+H⁺, 100%); NMR δH (d₆-DMSO) 0.88-0.98 (6H, m),1.31-1.38 (2H, m), 1.57-1.71 (4H, m), 2.27-2.41 (2H, m), 2.90-2.93 (1H,m), 3.04-3.10 (2H, m), 3.46-3.52 (1H, m), 4.17-4.18 (1H, m), 4.27-4.29(2H, m), 4.42-4.46 (1H, m), 4.97-5.06 (2H, m), 5.19 (1H, d), 6.95-6.99(1H, m), 8.03-8.06 (2H, m), 8.54 (1H, t), 8.99 (1H, t).

EXAMPLE 79[1S-[1α,2β,3β,4α(trans)]]-2,3-Dihydroxy-N-(2-Hydroxyethyl)-4-[5-[[(4-trifluoromethyl)phenyl]thio]-7-[(2-phenylcyclopropyl)amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboamide

Prepared according to the method of example 20, step a) using theproduct of example 5.

MS (APCI) 616 (M+H⁺, 100%); NMR δH (d₆-DMSO) 9.44 (1H, d), 7.93-7.60(4H, m), 7.29-7.06 (5H, m), 5.11 (1H, d), 4.95-4.91 (2H, m), 4.67 (1H,t), 4.38-4.34 (1H, m), 4.04 (1H, q), 3.41 (2H, q), 3.16 (2H, q),3.08-3.04 (1H, m), 2.80-2.75 (1H, m), 2.35-2.17 (3H, m), 1.41-1.37 (1H,m), 1.13 (1H, q).

EXAMPLE 80[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-[(3,4-dihydroxyphenyl)methyl]-cyclopentanecarboxamide.

Prepared according to the method of example 20, step a) using theproduct of example 2 and 3,4-dihydroxybenzylamine hydrochloride.

NMR δH (d₆-DMSO) 9.05 (1H, t), 8.75 (1H, br s), 8.29 (1H, br s), 6.65(2H, m), 6.52 (1H, d), 4.99 (2H, m), 4.47 (1H, m), 4.13 (2H, m), 3.51(2H, q), 3.32 (2H, s), 3.10 (2H, m), 2.80 (1H, m), 2.30 (2H, m), 1.69(2H, m), 1.58 (2H, m), 1.36 (2H, m), 0.99 (3H, t), 0.91 (3H, t).

EXAMPLE 81[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-[(2-hydroxyphenyl)methyl]-cyclopentanecarboxamide.

a) 2-Hydroxyphenylmethylamine, hydrobromide

Prepared according to the method of example 75, step a) using2-methoxybenzylamine.

NMR δH (d₆-DMSO) 9.55 (1H, s), 8.99 (1H, t), 8.36 (1H, t), 7.10 (1H, m),6.77 (1H, m), 5.16 (1H,d), 5.03 (1H, d), 4.95 (1H, d), 4.42 (1H, m),4.24 (2H, m), 4.17 (1H, m), 3.90 (2H, q), 3.09 (2H, m), 2.85 (1H, m),2.35 (2H, m), 1.69 (2H, m), 1.60 (2H, m), 1.36 (3H, m), 0.98 (3H, m),0.91 (3H, m).

b)[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-[(2-hydroxyphenyl)methyl]-cyclopentanecarboxamide.

Prepared according to the method of example 59, step a) using theproduct of example 2 and product of step a).

NMR δH (d₆-DMSO) 9.55 (1H, s), 8.99 (1H, t), 8.36 (1H, t), 7.10 (2H, d),6.77 (1H, m), 5.16 (1H, d), 5.03 (1H, d), 4.95 (1H, m), 4.42 (1H, m),4.17 (3H, m), 3.51 (2H, q), 3.09 (2H, m), 2.85 (1H, m), 2.35 (2H, m),1.69 (2H, m), 1.60 (2H, m), 1.36 (2H, m), 0.98 (3H, t), 0.91 (3H, t).

EXAMPLE 82[1S-(1α,2β,3β,4α)]-2,3-Dihydroxy-N-[2-hydroxyethyl]-4-[7-[(4-phenylbutyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxamide

Prepared according to the method of example 59, step a) using theproduct of example 66, step a) and ethanolamine, followed by the methodof example 1, step i).

MS (APCI) 530 (M+H⁺); NMR δH (d₆-DMSO) 9.01 (1H, t), 7.92-7.90 (1H, m),7.27-7.15 (5H, m), 5.12 (1H, d), 4.98-4.93 (2H, m), 4.67 (1H, t),4.43-4.41 (1H, m), 4.10-4.09 (1H, m), 3.53-3.51 (2H, m), 3.43-3.38 (2H,m), 3.17-3.05 (4H, m), 2.78-2.77 (1H, m), 2.63-2.59 (2H, m), 2.24 (2H,m), 1.71-1.63 (6H, m), 0.98 (3H, t).

EXAMPLE 83[1S-(1α,2β,3β,4α)]-4-[7-(Cyclopropylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-(2-hydroxyethyl)-cyclopentanecarboxamide

a)[3aR-(3aα,4α,6α,6aα)]-6-[7-(Cyclopropylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-N-(2-hydroxyethyl)-2,2-dimethyl-4N-cyclopenta-1,3-dioxole-4-carboxamide

Prepared according to the method of example 59, step a) using theproduct of example 3, step a).

MS (APCI) 478 (M+H⁺).

a)[1S-(1α,2β,3β,4α)]-4-[7-Cyclopropylamino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-(2-hydroxyethyl)-cyclopentanecarboxamide

Prepared according to the method of example 1, step i) using the productof step a).

MS (APCI) 438 (M+H⁺); NMR δH (d₆-DMSO) 9.10 (1H, d), 7.93 (1H, t),5.01-4.90 (1H, m), 4.51-4.40 (1H, m), 4.16-4.11 (1H, m), 3.42 (2H, t),3.25-3.00 (5H, m), 2.76 (1H, td), 2.39-2.21 (2H, m), 1.80-1.65 (2H, m),0.98 (3H, t), 0.90-0.65 (4H, m).

EXAMPLE 84[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-[(3-hydroxyphenyl)methyl]-cyclopentanecarboxamide

Prepared according to the method of example 59, step a) using theproduct of example 2 and 3-hydroxyphenylmethylamine.

MS (APCI) 516 (M+H⁺); NMR δH (d₆-DMSO) 9.28 (1H, s), 8.59 (1H, t), 8.36(1H, t), 7.05 (1H,t), 6.64-6.51 (3H, m), 5.11 (1H, d), 4.97 (1H,d), 4.94(1H, m), 4.40 (1H, m), 4.18 (2H,d), 4.12 (1H, m), 3.46 (2H, q),3.10-3.00 (2H, m), 2.85-2.75 (1H, m), 2.40-2.30 (1H,m), 2.28-2.20 (1H,m), 1.68-1.63 (2H, m), 1.58-1.54 (2H, m), 0.94 (3H, t), 0.87 (3H, t).

EXAMPLE 85[1S-[1α,2β,3β,4α(1S*,2R*)]]-4-[7-[[2-(4-Chlorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid

a)[1R-[1α(S*),2β]]-N-[2-(4-Chlorophenyl)cyclopropyl]-2-methoxy-2-phenyl-acetamideand[1S-[1α(R*),2β]]-N-[2-(4-Chlorophenyl)cyclopropyl]-2-methoxy-2-phenyl-acetamide

Oxalyl chloride (4.00 ml) was added to a solution of(S)-α-methoxyphenylacetic acid (2.00 g) in dichloromethane (100 ml)/DMF(10 ml). The reaction mixture was stirred at room temperature for 4hours then concentrated and the residue azeotroped with dichloromethane(3×10 ml). The resulting oil was taken into dichloromethane (4 ml) andtreated with a solution of ²-(⁴-chlorophenyl)cyclopropylamine (Preparedas described by C Kaiser etal J. Med. Pharm. Bul., 1962, 5, 1243) (1.86g) in pyridine (8 ml). The reaction mixture was stirred at roomtemperature for 30 minutes then partitioned between dichloromethane (500m1) and water (500 ml). The organic phase was dried and concentrated andthe residue purified (SiO₂, isohexane:ethyl acetate:acetic acid 66:33:1)to afford[1S-[1α(R*),2β]]-N-[2-(4-Chlorophenyl)cyclopropyl]-2-methoxy-2-phenyl-acetamide(1.23 g)

MS (APCI, negative ionization) 314 (M−H⁺, 100%).

Further elution of the column gave[1R-[1α(S*),2β]]-N-[2-(4-Chlorophenyl)cyclopropyl]-2-methoxy-2-phenyl-acetamide(1.40 g).

MS (APCI, negative ionization) 314 (M−H⁺, 100%).

b) (1R-trans)-2-(4-Chlorophenyl)-cyclopropylamine

A solution of[1R-[1α(S*),2β]]-N-[2-(4-Chlorophenyl)cyclopropyl]-2-methoxy-2-phenyl-acetamide(1.10 g) (prepared as described in step a)) in 1,4-dioxane (20 ml)containing 5M HCl (aq) (40 ml) was heated at reflux for 18 hours. Thereaction was concentrated and the residue partitioned between water anddiethyl ether. The aqueous phase was treated with 2M aqueous sodiumhydroxide solution (100 ml) then extracted with diethyl ether (2×100ml). The organic phase was concentrated to afford the sub-title compound(0.55 g). Optical rotation −138.3° (c=0.2, methanol).

c)[3aR-[3aα,4α,6α(1(R*,2S*),6α]]-6-[7-[[2-(4-Chlorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxylicacid

Prepared according to the method of example 1, step g) using the productof example 1, step f) and the product of step b).

MS (APCI) 547, 545 (M+H⁺), 545 (100%).

d)[1S-[1α,2β,3β,4α(1S*,2R*)]]-4-[7-[[2-(4-Chlorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid

Prepared according to the method of example 1, step i) using the productof step c).

MS (APCI) 507, 505 (M+H⁺), 505 (100%); NMR δH (d₆-DMSO) 9.37 (1H, d),7.33 (2H, d), 7.22 (2H, d), 5.01 (1H, q), 4.41 (1H, q), 4.22 (1H, t),3.18-3.15 (1H, m), 2.96-2.90 (1H, m), 2.87-2.80 (2H, m), 2.50-2.45 (1H,m), 2.38-2.30 (1H, m), 2.15-2.11 (1H, m), 1.56-1.47 (3H, m), 1.38-1.33(1H, m), 0.81 (3H, t).

EXAMPLE 86[1S-[1α,2β,3β,4α(1S*,2R*)]-4-[7-[[2-(4-Chlorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide

Prepared according to the method of example 63, step a) using theproduct of example 85, step d).

MS (APCI) 506, 504 (M+H⁺), 504 (100%); NMR δH (d₆-DMSO) 9.36 (1H, d),7.38 (1H, s), 7.34 (2H, d), 7.22 (2H, m), 6.92 (1H, m), 5.14 (1H, d),5.02-.4.94 (2H, m), 4.42-4.39 (1H, m), 4.13-4.11 (1H, m), 3.19-2.95 (1H,m), 2.92-2.74 (3H, m), 2.35-2.24 (2H, m), 2.15-2.11 (1H, m), 1.57-1.45(3H, m), 1.38-1.33 (1H, m), 0.81 (3H, t).

EXAMPLE 87[1S-[1α,2β,3β,4α(1R*,2S*)]]-4-[7-[[2-(4-Chlorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid

a) (1S-trans)-2-(4-Chlorophenyl)cyclopropylamine

Prepared according to the method of example 85, step b) using[1S-[1α(R*),2β]]-N-[2-(4-Chlorophenyl)cyclopropyl]-2-methoxy-2-phenyl-acetamide(the product of example 85, step a).

Optical rotation +159.0° (c=0.2, methanol).

b)[3aR-[3aα,4α,6α(1S*,2R*),6aα]]-6-[7-[[2-(4-Chlorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxylicacid

Prepared according to the method of example 1, step g) using the productof example 1, step f) and the product of step a).

MS (APCI) 547, 545 (M+H⁺), 545 (100%).

b)[1S-[1α,2β,3β,4α(1R*,2S*)]]-4-[7-[[2-(4-Chlorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid

Prepared according to the method of example 1, step i) using the productof step b).

MS (APCI) 507, 505 (M+H⁺), 505 (100%); NMR δH (d₆-DMSO) 12.43 (1h, brs), 9.36 (1H, d), 7.34 (2H, d), 7.23 (2H, d), 5.19-5.16(2H, m), 5.01(1H, q), 4.43-4.38 (1H, m), 4.23-4.20 (1H, m), 3.18-3.15 (1H, m),2.92-2.80 (3H, m), 2.50-2.27 (2H, m), 2.15-2.11 (1H, m), 1.56-1.46 (3H,m), 1.38-1.33 (1H, m), 0.81 (3H, t).

EXAMPLE 88[1S-[1α,2β,3β,4α(1S*,2R*)]]-2,3-Dihydroxy-4-[5-(methylthio)-7-[(2-phenylcyclopropyl)amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxylicacid

a) 4,6-Dihydroxy-2-(methylthio)-pyrimidine

Prepared according to the method of example 1, step a), usingiodomethane.

MS (APCI) 159 (M+H⁺, 100%).

b) 4,6-Dihydroxy-2-(methylthio)-5-nitro-pyrimidine

Prepared according to the method of example 1, step b), using theproduct of step a).

MS (APCI, negative ionization) 202 (M−H⁺, 100%).

c) 4,6-Dichloro-2-(methylthio)-5-nitro-pyrimidine

Prepared according to the method of example 1, step c), using theproduct of step b).

m. pt. 59° C.

d)(3aS-(3aα,4β,7β,7aα)]-5-[6-Chloro-2-(methylthio)-5-nitro-pyrimidin-4-yl]-tetrahydro-2,2-dimethyl-4,7-methano-1,3-dioxolo[4,5-c]pyridin-6(3aH)-one

Prepared according to the method of example 1, step d), using theproduct of step c).

MS (APCI) 389, 387 (M+H⁺), 387 (100%).

e)[3aR-(3aα,4α,6α,6aα)]-6-[[5-Amino-6-chloro-2-(methylthio)-4-pyrimidinyl]amino]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxylicacid

Prepared according to the method of example 1, step e), using theproduct of step d).

MS (APCI) 375 (M+H⁺, 100%).

f)[3aR-(3aα,4α,6α,6aα))]-6-[7-Chloro-5-(methylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxylicacid

Prepared according to the method of example 1, step f), using theproduct of step e).

MS (APCI) 388, 386 (M+H⁺), 386 (100%).

g)[3aR-[3aα,4α,6α(R*S*),6aα]]-Tetrahydro-2,2-dimethyl-6-[5-(methylthio)-7-[(2-phenylcyclopropyl)amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yi]-4H-cyclopenta-1,3-dioxole-4-carboxylicacid

Prepared according to the method of example 34, step a) using theproduct of step f).

MS (APCI) 483 (M+H⁺, 100%).

h)[1S-[1α,2β,3β,4α(1S*,2R*)]]-2,3-Dihydroxy-4-[5-(methylthio)-7-[(2-phenylcyclopropyl)amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxylicacid

Prepared according to the method of example 1, step i) using the productof step g).

MS (APCI) 443 (M+H⁺, 100%); NMR δH (d₆-DMSO) 7.31-7.15 (5H, m), 5.00(1H, q), 4.43 (1H, q), 4.19 (1H, t), 3.19 (1H, m), 2.68 (1H, m), 2.37(1H, m), 2.32 (3H, s), 2.12 (1H, m), 1.87 (2H, s), 1.50 (1H, m), 1.33(1H, m).

EXAMPLE 89[1S-[1α,2β,3β,4α(1S*,2R*)]]-2,3-Dihydroxy-4-[5-(methylthio)-7-[(2-phenylcyclopropyl)amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxamide

a)[3aR-[3aα,4α,6α(R*,S*),6aα]]-Tetrahydro-2,2-dimethyl-6-[5-(methylthio)-7-[(2-phenylcyclopropyl)amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-4H-cyclopenta-1,3-dioxole-4-carboxamide

Prepared according to the method of example 1, step h) using the productof example 88, step g).

MS (APCI) 481 (M+H⁺, 100%).

b)[1S-[1α,2β,3β,4α(1S*,2R*)]]-2,3-Dihydroxy-4-[5-(methylthio)-7-[(2-phenylcyclopropyl)amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxamide

Prepared according to the method of example 1, step i) using the productof step a).

MS (APCI) 442 (M+H⁺, 100%); NMR δH (d₆-DMSO) 9.36 (1H, d), 7.38 (1H, s),7.31-7.15 (5H, m), 6.92 (1H, d), 5.12 (1H, d), 4.98 (2H, m), 4.41 (1H,q), 4.13 (1H, q), 3.19 (2H, m), 2.76 (2H, m), 2.25 (2H, m), 2.13 (1H,m), 1.50 (1H, m), 1.32 (1H, m).

EXAMPLE 90 [1S-(1α,2β,3β,4α)]-2,3-Dihydroxy4-[7-[2-(phenylamino)ethylamino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxylicacid

Prepared according to the method of example 1, step g,) using theproduct of example 1, step f) and 2-(phenylaminoethylamine, followed bythe method of example 1, step i).

MS (APCI) 474 (M+H⁺, 100%).

EXAMPLE 91

a)[3aR-(3aα,4α,6α,6aα)]-6-[7-(Butylamino)-5-[(1-methyl)ethylthio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxylicacid

Prepared according to the method of example 11, step b), using theproduct of example 13, step a) and 2-propanethiol.

MS (APCI) 451 (M+H⁺, 100%).

b)[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-[(1-methyl)ethylthio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide

Prepared according to the method of example 1, step h), followed by themethod of example 1, step i) using the product of step a).

MS (APCI) 410 (M+H⁺, 100%); NMR δH (d₆-DMSO) 8.97 (1H, t), 7.36 (1H, s),6.91 (1H, s), 5.11 (1H, d), 4.93 (2H, m), 4.39 (1H, m), 4.10 (1H, m),3,91 (1H, m), 3.50 (2H, m), 2.33 (1H, m), 2.35-2.21 (2H, m), 1.62 (2H,m), 1.39 (8H, m), 0.91 (3H, m).

EXAMPLE 92[1S-(1α,2β,3β,4α)]-4-[7-[2-(4-Chlorophenyl)-ethylamino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid

a)(3aR-(3aα,4α,6α,6aα)]-6-[7-[2-(4-Chlorophenyl)-ethylaminol-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxylicacid

Prepared according to the method of example 1, step g), using theproduct of example 1, step f) and 2-(4-chlorophenyl)ethylamine.

MS (APCI) 535, 533 (M+H⁺), 533 (100%).

b)[1S-(1α,2β,3β,4α)]-4-[7-[2-(4-Chlorophenyl)-ethylamino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid

Prepared according to the method of example 1, step i), using theproduct of step a)

(APCI) 495, 493 (M+H⁺), 493 (100%).

EXAMPLE 93[1S-[1α,2β,3β,4α(E)]]-2,3-Dihydroxy-4-[7-(3-iodo-prop-2-enylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxylicacid

a)[3aR-[3aα,4α,6α(E),6aα]]-6-[7-(3-Tributylstannyl-prop-2-enylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyriuddin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxylicacid

Prepared according to the method of example 1, step g), using theproduct of example 1, step f) and (3-tributylstannyl)-prop-2-enylamine.

NMR δH (CDCl₃) 6.15 (1H, d), 5.92 (1H, d t), 5.65 (1H, m), 5.52 (1H, m),5.13 (1H, m), 4.39 (1H, m), 3.15 (2H, m), 2.95 (2H, m), 2.60 (1H, m),1.82 (2H, m), 1.58 (3H, s), 1.62-1.45 (9H, m), 1.39-1.28 (8H, m), 1.91(3H, t), 1.00-0.81 (15H, m).

b)[3aR-[3aα,4α,6α(E),6aα]]-Tetrahydro-6-[7-(3-iodo-prop-2-enylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxylicacid

A solution of iodine (0.18 g) in THF (1 ml) was added to a solution ofthe product of step a) (0.45 g) in THF (5 ml) at 0C. After 10 minutesthe reaction mixture was partitioned between ethyl acetate (50 ml) and10% sodium metabisulfite (aq) (50 ml). The organic layer was dried andconcentrated. Purification (SiO₂, diethyl ether as eluant) gave thesubtitle compound (0.21 g).

NMR δH (CDCl₃) 7.94 (1H, t), 6.43 (1H, d t), 6.30 (1H, d), 5.78 (1H, d),5.70 (1H, d), 5.12 (1H, d), 4.20 (1H, m), 3.56 (1H, m), 3.26-3.01 (4H,m), 2.62 (1H, m), 1.83 (2H, m), 1.65 (3H, s), 1.45 (3H, s), 1.10-0.81(3H, t).

c) [1S-[1α,2β,3β,4α(E)]]-2,3-Dihydroxy4-[7-(3-iodo-prop-2-enylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxylicacid

Prepared according to the method of example 1, step i), using theproduct of step b).

MS (APCI) 521 (M+H⁺, 100%); NMR δH (d₆-DMSO) 6.65 (1H, d t), 6.45 (1H,d), 4.98 (1H, q), 4.40 (1H, m), 4.26 (1H, m), 4.08 (2H, d), 3.20-3.00(2H, m), 2.75-2.65 (1H, m), 2.53-2.22 (2H, m), 1.68 (2H, m), 0.99 (3H,t).

Pharmacological Data

The preparation for the assay of the P_(2T)-receptor agonist/antagonistactivity in washed human platelets for the compounds of the inventionwas carried out as follows.

Human venous blood (100 ml) was divided equally between 3 tubes, eachcontaining 3.2% trisodium citrate (4 ml) as anti-coagulant. The tubeswere centrifuged for 15 minutes at 240 G to obtain a platelet-richplasma (PRP) to which 300 ng/ml prostacyclin was added to stabilize theplatelets during the washing procedure. Red cell free PRP was obtainedby centrifugation for 10 minutes at 125 G followed by furthercentrifugation for 15 minutes at 640 G. The supernatant was discardedand the platelet pellet resuspended in modified, Calcium Free Tyrodesolution (10 ml) (CFT), composition: NaCl 137 mM, NaHCO₃ 11.9 mM,NaH₂PO₄ 0.4 mM, KCl 2.7 mM, MgCl₂ 1.1 mM, dextrose 5.6 mM, gassed with95% 02/5% CO₂ and maintained at 37° C. Following addition of a further300 ng/ml PGI₂, the pooled suspension was centrifuged once more for 15minutes at 640 G. The supernatant was discarded and the plateletsresuspended initially in 10 ml CFT with further CFT added to adjust thefinal platelet count to 2×10⁵/ml. This final suspension was stored in a60 ml syringe at 3° C. with air excluded. To allow recovery fromPGI₂-inhibition of normal function, platelets were used in aggregationstudies no sooner than 2 hours after final resuspension.

In all studies, 3 ml aliquots of platelet suspension were added to tubescontaining CaCl₂ solution (60 gl of 50 mM solution with a finalconcentration of 1 mM). Human fibrinogen (Sigma, F 4883) and8-sulphophenyltheophylline (8-SPT which was used to block any P₁-agonistactivity of compounds) were added to give final concentrations of 0.2mg/ml (60 μl of 10 mg/ml solution of clottable protein in saline) and300 nM (10 μlof 15 mM solution in 6% glucose), respectively. Plateletsor buffer as appropriate were added in a volume of 150 μl to theindividual wells of a 96 well plate. All measurements were made intriplicate in platelets from each donor.

The agonist/antagonist potency was assessed as follows.

Aggregation responses in 96 well plates were measured using the changein absorbance given by the plate reader at 660 nm. Either a Bio-TecCeres 900C or a Dynatech MRX were used as the plate reader.

The absorbance of each well in the plate was read at 660 nm to establisha baseline figure. Saline or the appropriate solution of test compoundwas added to each well in a volume of 10 μl to give a finalconcentration of 0, 0.01, 0.1, 1, 10 or 100 mM. The plate was thenshaken for 5 min on an orbital shaker on setting 10 and the absorbanceread at 660 nm. Aggregation at this point was indicative of agonistactivity of the test compound. Saline or ADP (30 mM; 10 μl of 450 mM)was then added to each well and the plate shaken for a further 5 minbefore reading the absorbance again at 660 nm.

Antagonist potency was estimated as a % inhibition of the control ADPresponse to obtain an IC₅₀. Compounds of the invention have pIC₅₀ valuesof more than 5.0

What is claimed is:
 1. A compound of formula (I):

wherein; X is OH or NHR³; R¹ is C₁₋₆-alkyl, C₃₋₈-cycloalkyl or a phenylgroup, each group being optionally substituted by one or more halogenatoms and/or OR⁴, NR⁴R⁵, C₁₋₆-thioalkyl and/or C₁₋₆-alkyl (itselfoptionally substituted by one or more halogen atoms); R² is C₁₋₈-alkylor C₂₋₈-alkenyl each of which is optionally substituted by one or morehalogen atoms and/or OR⁴, NR⁴R⁵, C₁₋₆-thioalkyl, C₃₋₈-cycloalkyl, aryland/or C₁₋₆-alkyl groups; or R² is a C₃₋₈-cycloalkyl group optionallysubstituted by one or more halogen atoms and/or OR⁴, NR⁴R⁵,C₁₋₆-thioalkyl, phenyl and/or C₁₋₆-alkyl groups; the optional phenylsubstituent being further optionally substituted by one or more halogenatoms and/or NO₂, C(O)R⁴, OR⁴, NR⁴R⁵, C₁₋₆-thioalkyl and/or C₁₋₆-alkylgroups; R³ is hydrogen or C₁₋₆-alkyl substituted by one or more hydroxyand/or phenyl groups and optionally by one or more halogen atoms,wherein the phenyl group is substituted by one or more hydroxy groupsand optionally substituted by one or more halogen atoms and/or NO₂,C(O)R⁴, OR⁴, NR⁴R⁵, C₁₋₆-thioalkyl and/or C₁₋₆-alkyl groups, or R³ is aC₁₋₆-alkyl group substituted by a C(O)NR⁴R⁵ or a COOH group andoptionally by one or more halogen atoms and/or OR⁴, C(NH)NR⁴R⁵,C(O)NR⁴R⁵, phenyl and/or C₁₋₆-alkyl groups, wherein the alkyl group isoptionally substituted by one or more hydroxy and/or phenyl groups andwherein the phenyl group is optionally substituted as defined above forR³; or R³ is a lactam ring of formula (i):

 wherein Q is a (CH₂)_(m) moiety wherein m is 1, 2 or 3, Z is O, C(O) orCH₂; R⁴ and R⁵ each independently represent hydrogen, phenyl or aC₁₋₆-alkyl wherein the alkyl group is optionally substituted by one ormore phenyl groups; or a salt thereof.
 2. A compound according to claim1 in which R¹ is C₁₋₄-alkyl, C₄₋₈-cycloalkyl or a phenyl groupoptionally substituted by one or more halogen atoms or by a CF₃ group.3. A compound according to claim 1 in which R² is C₁₋₆-alkyl optionallysubstituted by phenyl or C₁₋₆-thioalkyl or R² is a C₃₋₈-cycloalkyl groupoptionally substituted by phenyl.
 4. A compound according to claim 1 inwhich X is OH or NHR³ where R³ is hydrogen or C₁₋₆-alkyl substituted byhydroxy and optionally by C(O)NH₂ or di-fluoro; C₁₋₆-alkyl substitutedby C(O)NH₂; C₁₋₆-alkyl substituted by C(O)NHMe; C₁₋₆-alkyl substitutedby hydroxyphenyl and optionally by C(O)NR⁴R⁵ or R³ is a lactam ring offormula:


5. A compound according to claim 1, which is[1S-(1α,2β,3β,4α)]-4-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide,[1S-(1α,2β,3β4α)]-4-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,3-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid,[1S(1α,2β,3β,4α)]-4-[7-(cyclopropylamino)-5-(propylthio)-3H-1,2,3-tiazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide,[1S-(1α,2β,3β,4α)]-4-[7-(cyclopropylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid,[1S-[1α,2β,3β,4α(trans)]]-2,3-dihydroxyy-4-[7-[(2-phenylcyclopropyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxylicacid,[1S-[1α,2β,3β,4α(trans)]]-2,3-dihydroxyy-4-[7-[(2-phenylcyclopropyl)-amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxamide,[1S-(1α,2β,3β,4α)]]-2,3-dihydroxy-4-[7-(2-phenylethylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxylicacid,[1S-(1α,2β,3β,4α)]-2,3-dihydroxy-4-[7-(2-phenylethylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxamide,[1S-(1α,2β,3β,4α)]-2,3-dihydroxy-4-[7-[2-(methylthio)ethylamino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxylicacid,[1S-(1α,2β,3β,4α)]-2,3-dihydroxy-4-[7-[2-(methylthilo)ethylamino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxamide,[1S-[1α,2β,3β,4α(trans)]]-4-[5-(Cyclohexylthio)-7-[2-phenylcyclopropyl)amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3dihydroxy-cyclopentanecarboxylicacid,[1S-[1α,2β,3β,4α(trans)]]-2,3-Dihydroxy-4-[7-[(2-phenylcyclopropyl)amino]-5-(cyclohexylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxamide,[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(3,4-dichilorophenylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid,[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(3,4-dichlorophenylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide,[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-[4-(trifluoromethyyl)phenylthio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid, and pharmaceutically acceptable salts thereof.
 6. A compoundaccording to claim 1, which is[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-[4-(trifluoromethyl)phenylthio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide,[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(phenylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid,[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(phenylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide,[1S-(1α,2β,3β,4α)]-4-[7-(Cyclopropylamino)-5-(3,4-dichlorophenylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide,[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-(2-hydroxyethyl)-cyclopentanecarboxamide,[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-(3-hydroxy-2,2-difluoropropyl)-cyclopentanecarboxamide,[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-[2-(4-hydroxyphenyl)ethyl]cyclopentanecarboxamide,[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-[4-(trifluoromethyl)phenylthio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-(2-hydroxyethyl)-cyclopentanecarboxamide,[1S-(1α,2β,3β,4α)]-N-[1-(Aminocarbonyl)-2-(hydroxy)ethyl]-4-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide,[1S-[1α(S*),2β,3β,4α]]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-N-(tetrahydro-3-oxo-isoxazol-4-yl)-2,3-dihydroxy-cyclopentanecarboxamide,[1S-[1α(R*),2β,3β,4α]]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-(2-oxo-pyrrolidin-3-yl)-cyclopentanecarboxamide,[1S-[1α(R*),2β,3β,4α]]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-(2,3-di-oxo-pyrrolidin-3-yl)-cyclopentanecarboxamide,[1S-[1α(R*),2β,3β,4α]]-N-[(Aminocarbonyl)-methyl]-4-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide,[1S-[1α(R*),2β,3β,4α]]-N-[1-(Aminocarbonyl)-2-(4-hydroxyphenyl)ethyl]-4-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide,and pharmaceutically acceptable salts thereof.
 7. A compound accordingto claim 1, which is[1S-[1α(R*),2β,3β,4α]]-N-[1-(Aminocarbonyl)-2-(hydroxylethyl]-4-[7-(butylamino)-5-[4-(trifluoromethyl)phenylthio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide,[1S-[1α(1R*,2S*),2β,3β,4α]]-N-[1-(Amino-carbonyl)-2-(hydroxy)propyl]-4-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxycyclopentanecarboxamide,[1S-[1α,2β,3β,4α]]-N-[2-(Aminocarbonyl)ethyl]-4-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxarnide,[1S-[1α,2β,3β,4α]]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-[2-(methylaminocarbonyl)-ethyl]-cyclopentanecarboxamide,[1S-[1α,2β,3β,4α(1S*,2R*)]]-2,3-Dihydroxy-4-[7-[(2-phenylcyclopropyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]cyclopentanecarboxylicacid,[1S-[1α,2β,3β,4α(1S*,2R*)]]-2,3-Dihydroxy-4-[7-[(2-phenylcyclopropyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxamide,[1S-(1α,2β,3β,4α)]-2,3-Dihydroxy-4-[7-(cyclobutylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxylicacid,[1S-(1α,2β,3β,4α)]-4-[7-(Cyclobutylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide,[1S-(1α,2β,3β,4α)]-4-[7-(Cyclopropylamino)-5-[[4-(trifluomomethyl)phenyl]thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid,[1S-(1α,2β,3β,4α)]-4-[7-(Cyclopropylamino)-5-[[4-(trifluoromethyl)phenyl]thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide,[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid,[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide,[1S-(1α,2β,3β,4α)]-2,3-Dihydroxy-4-7-[(1,4-dimethylpentyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxylicacid,[1S-(1α,2β,3β,4α)]-2,3-Dihydroxy-4-[7-[(1,4-dimethylpentyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]cyclopentanecarboxamide,[1S-(1α,2β,3β,4α)]-2,3-Dihydroxy-4-[7-[(1-methylbutyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxylicacid, and pharmaceutically acceptable salts thereof.
 8. A compoundaccording to claim 1, which is:[1S-(1α,2β,3β,4α)]-2,3-Dihydroxy-4-[7-[(1-methylbutyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxamide,[1S-(1α,2β,3β,4α)]-2,3-Dihydroxy-4-[7-[(1,3-dimethylbutyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxylicacid,[1S-(1α,2β,3β,4α)]-2,3-Dihydroxy-4-[7-[(1,3-dimethylbutyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]cyclopentanecarboxamide,[1S-(1α,2β,3β,4α)]-4-[7-(Ethylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid,[1S-(1α,2β,3β,4α)]-4-[7-(4-Hydroxybutylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid,[1S-(1α,2β,3β,4α)]-4-[7-(Cyclopentylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid,[1S-(1α,2β,3β,4α)]-4-[5-[(4-Bromophenyl)thio]-7-(butylamino)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid,[1S-(1α,2β,3β,4α)]-4-[7-[(6-Hydroxyhexyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid,[1S-[1α,2β,3β,4α(trans)]]-2,3-Dihydroxy-4-[5-[[4-(trifluoromethyl)phenyl]thio]-7-[(2-phenylcyclopropyl)amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxylicacid,[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(cyclopentylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxylicacid,[1S-(1α,2β,3β,4α)]-2,3-Dihydroxy-4-[7-[(3-methylbutyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxylicacid,[1S-[1α,2β,3β,4α(1R*,2S*)]]-2,3-Dihydroxy-4-[7-[(2-phenylcyclopropyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxylicacid,[1S-[1α(R*),2β,3β,4α]]-N-(3-Amino-3-oxo-2-propyl)-4-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentylcarboxamide,[1S-[1α(R*),2β,3β,4α]]-3-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-[3-hydroxy-1-(methylamino)-1-oxo-2-propyl]-cyclopentanecarboxamide,[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-[3-(dimethylamino)-3-oxo-propyl]-cyclopentanecarboxamide,and pharmaceutically acceptable salts thereof.
 9. A compound accordingto claim 1, which is[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-[2-(dimethylamino)-2-oxo-ethyl)-cyclopentanecarboxamide,[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxyl-N-[3-oxo-3-[(phenylmethyl)amino]-propyl]-cyclopentanecarboxamide,[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-2-(methylamino)-2-oxo-ethyl)-cyclopentanecarboxamide,[1S-(1α(R*),2β,3β,4α)]-N-[4-Amino-1-(aminocarbonyl)-4-oxo-butyl]-4-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3yl]-2,3-dihydroxy-cyclopentanecarboxamide,[1S-(1α,2β,3β,4α)]-N-[4-Amino-1-[(methylamino)carbonyl]-4-oxo-butyl]-4-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide,[1S-(1α(R*),2β,3β,4α)]-N-[1-(Aminocarbonyl)-3-hydroxy-propyl)-4-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide,[1S-(1α(R*),2β,3β,4′)]-N-[1-(Aminocarbonyl)-2-hydroxy-ethyl)-2,3-dihydroxy-4-[7-[(4-phenylbutyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxamide,1S-[1α,2β,3β,4α(1S*,2R*)]-N-[(Aminocarbonyl)methyl]-2,3-dihydroxy-4-[7-[(2-phenylcyclopropyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxamide,[1S-(1α(R*),2β,3β,4α)]-N-[(1-Aminocarbonyl)-4-(methylamino)-4-oxo-butyl]-4-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-cyclopentanecarboxamide,[1S-(1α,2β,3β,4α)]-2,3-Dihydroxy-4-[7-[(4-phenylbutyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxylicacid,[1S-(1α,2β,3β,4α)]-2,3-Dihydroxy-4-[7-[(1-phenylcyclopropyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxylicacid,[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-(2,3-dihydroxypropyl)-cyclopentanecarboxamide,[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]-cyclopentanecarboxamide,[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-propylthio)-3H-1,2,3-triazoio[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-[2-hydroxy-2-(3-hydroxyphenyl)ethyl]-cyclopentanecarboxamide,and pharmaceutically acceptable salts thereof.
 10. A compound accordingto claim 1, which is[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-[(4-hydroxy-3-methoxyphenyl)-methyl]-cyclopentanecarboxamide,[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-[(4-hydroxyphenyl)-methyl]-cycylopentanecarboxamide,[1S-[1α,2β,3β,4α(1R*,2S*)]]-2,3-Dihydroxy-N-(2-hydroxyethyl)-4-[7-[(2-phenylcyclopropyl)amino]-5-propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxamide,[1S-[1α,2β,3β,4α(1S*,2R*)]]-2,3-Dihydroxy-N-(2-hydroxyethyl)-4-[7-[(2-phenylcyclopropyl)amino]-5-propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxamide,[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-[(2-hydroxy-5-nitrophenyl)methyl]-cyclopentanecarboxamide,[1S-[1α,2β,3β,4α(trans)]]-2,3-Dihydroxy-N-(2-Hydroxyethyl)-4-[5-[[(4-trifluoromethyl)phenyl]thio]-7-[(2-phenylcyclopropyl)amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-y]-cyclopentanecarboaxmide,[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-[(3,4-dihydroxyphenyl)methyl]-cyclopentanecarboxamide,[1S-(1α,2β,3β,4α)]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-[(2-hydroxyphenyl)methyl]-cyclopentanecarboxamide,[1S-(1α,2β,3β,4α)]-2,3-Dihydroxy-N-[2-hydroxyethyl]-4-[7-[(4-phenylbutyl)amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentanecarboxamide,[1S-(1α,2β,3β,4α)]-4-[7-(Cyclopropylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,3-dihydroxy-N-(2-hydroxyethyl)-cyclopentanecarboxamide.11. A pharmaceutical composition comprising a compound according toclaim 1 in combination with a pharmaceutically acceptable diluent,adjuvent or carrier.
 12. A method for the treatment of unstable angina,coronary angioplasty (PTCA), perithrombolysis, primary arterialthrombotic complications due to interventions in atheroscleroticdisease, or thrombotic complications of surgical or mechanical damage,which comprises administering to a patient suffering from such adisorder a therapeutically effective amount of a compound according toclaim
 1. 13. A process for the preparation of a compound of formula (I)as defined in claim 1 which comprises (a) deprotecting a compound offormula (II):

 wherein R¹ and R² are as defined above, P¹ is a protecting group and Yis X as defined above or O—C₁₋₆-alkyl, O-benzyl or NHR⁷ wherein R⁷ is aC₁₋₆-alkyl group substituted by a C(O)OR⁸ group and optionally one ormore halogen atoms and/or OR⁴, C(NH)NR⁴R⁵, C(O)NR⁴R⁵, phenyl and/orC₁₋₆-alkyl groups, wherein R⁴ and R⁵ are as defined above and R⁸ isC₁₋₆-alkyl or benzyl; and, optionally (b) reacting the compound offormula (I) thus obtained with a suitable acid or base to prepare apharmaceutically acceptable salt.
 14. A compound of formula (II) asdefined in claim 13.